649 results on '"Nav1.7"'
Search Results
2. NaV1.7 channels are expressed in the lower airways of the human respiratory tract
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Hernández-Plata, Everardo, Cruz, Ana Alfaro, and Becerril, Carina
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- 2023
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Catalog
3. NAN-190, a 5-HT1A antagonist, alleviates inflammatory pain by targeting Nav1.7 sodium channels
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Li, Shaohua, Jin, Yuchen, Li, Min, and Yu, Haibo
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- 2023
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4. Small molecule targeting Na V 1.7 via inhibition of CRMP2-Ubc9 interaction reduces pain-related outcomes in a rodent osteoarthritic model.
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Hestehave, Sara, Allen, Heather N., Gomez, Kimberly, Duran, Paz, Calderon-Rivera, Aida, Loya-López, Santiago, Rodríguez-Palma, Erick J., and Khanna, Rajesh
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PATCH-clamp techniques (Electrophysiology) , *DORSAL root ganglia , *BEHAVIORAL assessment , *SODIUM channels , *SMALL molecules - Abstract
Supplemental Digital Content is Available in the Text. Compound 194 inhibits CRMP2 SUMOylation, indirectly regulating NaV1.7 to alleviate osteoarthritic pain. Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel NaV1.7. We previously identified compound 194 as an indirect inhibitor of NaV1.7 by preventing SUMOylation of the NaV1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of NaV1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene–related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of NaV1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194. [ABSTRACT FROM AUTHOR] more...
- Published
- 2025
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5. Optimizing Nav1.7‐Targeted Analgesics: Revealing Off‐Target Effects of Spider Venom‐Derived Peptide Toxins and Engineering Strategies for Improvement.
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Luo, Sen, Zhou, Xi, Wu, Meijing, Wang, Gongxin, Wang, Li, Feng, Xujun, Wu, Hang, Luo, Ren, Lu, Minjuan, Ju, Junxian, Wang, Wenxing, Yuan, Lei, Luo, Xiaoqing, Peng, Dezheng, Yang, Li, Zhang, Qingfeng, Chen, Minzhi, Liang, Songping, Dong, Xiuming, and Hao, Guoliang more...
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PEPTIDES , *NEURALGIA , *PHARMACOPHORE , *TOXINS , *SPIDER venom , *CARDIOTOXICITY - Abstract
The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom‐derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX‐III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore‐guided rational design is employed for the development of an mGpTx1 analogue, mGpTx1‐SA, which retains its inhibition of hNav1.7 while significantly reducing its inhibition of rKv4.2/4.3 and eliminating cardiotoxicity. Moreover, mGpTx1‐SA demonstrates potent analgesic effects in both inflammatory and neuropathic pain models, accompanied by an improved in vivo safety profile. The results suggest that off‐target inhibition of rKv4.2/4.3 by specific spider peptide toxins targeting hNav1.7 may arise from a conserved binding motif. This insight promises to facilitate the design of hNav1.7‐specific analgesics, aimed at minimizing rKv4.2/4.3 inhibition and associated toxicity, thereby enhancing their suitability for therapeutic applications. [ABSTRACT FROM AUTHOR] more...
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- 2024
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6. SCN9A and SCN10A Polymorphism and Therapeutic Effectiveness of Lidocaine Local Anesthetic Injection in Subjects with Diabetic Neuropathy Pain.
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Harsa, I. Made Subhawa, Andiani, Sulistiawati, Herawati, Lilik, Hidayati, Hanik Badriyah, and Kuntaman
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DIABETIC neuropathies , *LOCAL anesthetics , *SODIUM channels , *LIDOCAINE , *PAIN management - Abstract
Background: Diabetic neuropathy pain (DNP) is one of the complications experienced by more than half of the diabetic population. Treatment using lidocaine injection is one of the effective ways to manage pain in patients with DNP. Pain therapy using lidocaine locally targets the SCN9A and SCN10A genes, which encode the sodium receptors Nav1.7 and Nav1.8. The effect of lidocaine inhibits these sodium channels to reduce pain transmission. Purpose: This study aims to analyze the effect of polymorphism of genes encoding Nav1.7 and Nav1.8 on the effectiveness of lidocaine local injection therapy in patients with DNP. Methods: This study was an analytic observational study with a cross-sectional approach. A total of 63 people with DNP were genotyped for the SCN9A rs 6746030 gene and the SCN10A rs12632942 gene using Real-Time PCR/qPCR and DNA sequencing. Result: The results showed that 91.2% and 70.6% of the population who experienced decreased pain had the GA mutant allele in the SCN9A rs6746030 gene and the AG mutant allele in the SCN10A rs12632942 gene. The results showed a significant association of Nav1.7 and Nav1.8 gene polymorphisms with the effectiveness of lidocaine local anesthetic injection therapy in diabetic neuropathy pain patients (p < 0.05). Conclusion: This study shows that there was an association between Nav1.7 and Nav1.8 gene polymorphisms and the effectiveness of lidocaine local anesthetic injection therapy in patients with DNP. Lidocaine injection therapy that targets the Nav1.7 and Nav1.8 sodium channels involving the SCN9A and SCN10A genes can be a therapeutic alternative for patients with DNP. [ABSTRACT FROM AUTHOR] more...
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- 2024
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7. Small Fiber Neuropathy in Burning Mouth Syndrome: A Systematic Review.
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Kouri, Maria, Adamo, Daniela, Vardas, Emmanouil, Georgaki, Maria, Canfora, Federica, Mignogna, Michele Davide, and Nikitakis, Nikolaos
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BURNING mouth syndrome , *PAIN threshold , *OROFACIAL pain , *NERVE fibers , *GENE expression , *BLINKING (Physiology) - Abstract
Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain disorder, characterized by persistent burning sensations and pain without clear pathological causes. Recent research suggests that small fiber neuropathy (SFN) may play a significant role in the neuropathic pain and sensory disturbances associated with BMS. Following PRISMA guidelines, this systematic review aims to evaluate and synthesize current evidence supporting SFN's involvement in BMS. The protocol is registered in PROSPERO (CRD42024555839). The results show eight studies reported reductions in nerve fiber density in tongue biopsies (ranging from 30% to 60%), along with morphological changes indicative of small fiber damage. Additionally, an increase in TRPV1-positive, NGF-positive, and P2X3-positive fibers, overexpression of Nav1.7, and slight underexpression of Nav1.9 mRNA were observed in BMS patients. Quantitative Sensory Testing in seven studies revealed sensory abnormalities such as reduced cool detection and cold pain thresholds. Blink reflex and corneal confocal microscopy also indicated peripheral and central small fiber damage, along with increased artemin mRNA expression. The evidence strongly supports SFN as a key factor in the pathophysiology of BMS, particularly due to reductions in nerve fiber density and altered sensory thresholds. However, variability across studies highlights the need for larger, standardized research to establish causal relationships and guide therapeutic strategies. [ABSTRACT FROM AUTHOR] more...
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- 2024
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8. Cannabigerol Reduces Acute and Chronic Hypernociception in Animals Exposed to Prenatal Hypoxia-Ischemia.
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Rezende, Bismarck, Marques, Kethely Lima, de Carvalho, Filipe Eloi Alves, Gonçalves, Vitória Macario de Simas, de Oliveira, Barbara Conceição Costa Azeredo, Nascimento, Gabriela Guedes, dos Santos, Yure Bazilio, Antunes, Fernanda, Barradas, Penha Cristina, Fontes-Dantas, Fabrícia Lima, and Montes, Guilherme Carneiro more...
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SPINAL nerves , *PAIN management , *ANALGESICS , *NEURALGIA , *CHRONIC pain - Abstract
Cannabigerol (CBG), a phytocannabinoid, has shown promise in pain management. Previous studies by our research group identified an increase in pain sensitivity as a consequence of prenatal hypoxia-ischemia (HI) in an animal model. This study aimed to investigate the efficacy of CBG in acute and chronic hyperalgesia induced by prenatal HI. A pharmacological screening was first conducted using hot plate and open-field tests to evaluate the antinociceptive and locomotor activities of animals administered with a 50 mg/kg oral dose of cannabis extract with a high CBG content. Prenatal HI was induced in pregnant rats, and the offspring were used to evaluate the acute antinociceptive effect of CBG in the formalin-induced peripheral pain model, while chronic antinociceptive effects were observed through spinal nerve ligation (SNL) surgery, a model used to induce neuropathic pain. Our results show that CBG exhibited an antinociceptive effect in the hot plate test without affecting the animals' motor function in the open-field test. CBG significantly reduced formalin-induced reactivity in HI offspring during both the neurogenic and inflammatory phases. CBG treatment alleviated thermal and mechanical hypernociception induced by SNL. Biomolecular analysis revealed CBG's ability to modulate expression, particularly reducing TNFα and Nav1.7 in HI male and female rats, respectively. These results highlight CBG as a potential antinociceptive agent in acute and chronic pain models, suggesting it as a promising therapeutic option without inducing motor impairment. Further research is needed to fully elucidate its mechanisms and clinical applications in pain management. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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9. ST‐2560, a selective inhibitor of the NaV1.7 sodium channel, affects nocifensive and cardiovascular reflexes in non‐human primates.
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Mulcahy, John V., Beckley, Jacob T., Klas, Sheri D., Odink, Debra A., Delwig, Anton, Pajouhesh, Hassan, Monteleone, Dennis, Zhou, Xiang, Du Bois, Justin, Yeomans, David C., Luu, George, and Hunter, John C. more...
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AUTONOMIC nervous system , *DIASTOLIC blood pressure , *AUTONOMIC ganglia , *SODIUM channels , *DRUG discovery - Abstract
Background and Purpose: The voltage‐gated sodium channel isoform NaV1.7 is a high‐interest target for the development of non‐opioid analgesics due to its preferential expression in pain‐sensing neurons. NaV1.7 is also expressed in autonomic neurons, yet its contribution to involuntary visceral reflexes has received limited attention. The small molecule inhibitor ST‐2560 was advanced into pain behaviour and cardiovascular models to understand the pharmacodynamic effects of selective inhibition of NaV1.7. Experimental Approach: Potency of ST‐2560 at NaV1.7 and off‐target ion channels was evaluated by whole‐cell patch‐clamp electrophysiology. Effects on nocifensive reflexes were assessed in non‐human primate (NHP) behavioural models, employing the chemical capsaicin and mechanical stimuli. Cardiovascular parameters were monitored continuously in freely‐moving, telemetered NHPs following administration of vehicle and ST‐2560. Key Results: ST‐2560 is a potent inhibitor (IC50 = 39 nM) of NaV1.7 in primates with ≥1000‐fold selectivity over other isoforms of the human NaV1.x family. Following systemic administration, ST‐2560 (0.1–0.3 mg·kg−1, s.c.) suppressed noxious mechanical‐ and chemical‐evoked reflexes at free plasma concentrations threefold to fivefold above NaV1.7 IC50. ST‐2560 (0.1–1.0 mg·kg−1, s.c.) also produced changes in haemodynamic parameters, most notably a 10‐ to 20‐mmHg reduction in systolic and diastolic arterial blood pressure, at similar exposures. Conclusions and Implications: Acute pharmacological inhibition of NaV1.7 is antinociceptive, but also has the potential to impact the cardiovascular system. Further work is merited to understand the role of NaV1.7 in autonomic ganglia involved in the control of heart rate and blood pressure, and the effect of selective NaV1.7 inhibition on cardiovascular function. [ABSTRACT FROM AUTHOR] more...
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- 2024
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10. Therapeutic targeting of voltage-gated sodium channel NaV1.7 for cancer metastasis.
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Pukkanasut, Piyasuda, Jaskula-Sztul, Renata, Carlos Gomora, Juan, and Velu, Sadanandan E.
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SODIUM channels ,METASTASIS ,CANCER cell migration ,SMALL molecules ,CANCER cell proliferation ,CELL migration - Abstract
This review focuses on the expression and function of voltage-gated sodium channel subtype Na
V 1.7 in various cancers and explores its impact on the metastasis driving cell functions such as proliferation, migration, and invasiveness. An overview of its structural characteristics, drug binding sites, inhibitors and their likely mechanisms of action are presented. Despite the lack of clarity on the precise mechanism by which NaV 1.7 contributes to cancer progression and metastasis; many studies have suggested a connection between NaV 1.7 and proteins involved in multiple signaling pathways such as PKA and EGF/EGFR-ERK1/2. Moreover, the functional activity of NaV 1.7 appears to elevate the expression levels of MACC1 and NHE-1, which are controlled by p38 MAPK activity, HGF/c-MET signaling and c-Jun activity. This cascade potentially enhances the secretion of extracellular matrix proteases, such as MMPs which play critical roles in cell migration and invasion activities. Furthermore, the NaV 1.7 activity may indirectly upregulate Rho GTPases Rac activity, which is critical for cytoskeleton reorganization, cell adhesion, and actin polymerization. The relationship between NaV 1.7 and cancer progression has prompted researchers to investigate the therapeutic potential of targeting NaV 1.7 using inhibitors. The positive outcome of such studies resulted in the discovery of several inhibitors with the ability to reduce cancer cell migration, invasion, and tumor growth underscoring the significance of NaV 1.7 as a promising pharmacological target for attenuating cancer cell proliferation andmetastasis. The research findings summarized in this review suggest that the regulation of NaV 1.7 expression and function by small molecules and/or by genetic engineering is a viable approach to discover novel therapeutics for the prevention and treatment of metastasis of cancerswith elevated NaV 1.7 expression. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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11. Intranasal CRMP2-Ubc9 inhibitor regulates NaV1.7 to alleviate trigeminal neuropathic pain.
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Loya-Lopez, Santiago I., Allen, Heather N., Duran, Paz, Calderon-Rivera, Aida, Gomez, Kimberly, Kumar, Upasana, Shields, Rory, Zeng, Rui, Dwivedi, Akshat, Saurabh, Saumya, Korczeniewska, Olga A., and Khanna, Rajesh more...
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NEURALGIA , *DORSAL root ganglia , *SENSORY neurons , *SENSORY ganglia , *TRIGEMINAL nerve diseases , *SODIUM channels , *OROFACIAL pain - Abstract
Dysregulation of voltage-gated sodium NaV1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/NaV1.7 interaction and increased functional activity of NaV1.7. Targeting this feed-forward regulation, we developed compound 194, which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of NaV1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we used a comprehensive array of approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of NaV1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a, Dpysl2, and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and NaV1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/NaV1.7 interaction, impeded NaV1.7 diffusion on the plasma membrane, and subsequently diminished NaV1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve, 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating NaV1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain. [ABSTRACT FROM AUTHOR] more...
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- 2024
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12. Role of macrophages in trigeminal ganglia in ectopic orofacial pain associated with pulpitis.
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Sunaga, Miki, Tsuboi, Yoshiyuki, Kaizu, Akihiro, and Shinoda, Masamichi
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This study aimed to elucidate the role of macrophages in the trigeminal ganglia (TG) in developing pulpitis-associated ectopic orofacial pain. Rats underwent maxillary pulp exposure, and Fluoro-Gold (FG) was administered in the ipsilateral whisker pad (WP). Head withdrawal threshold (HWT) upon mechanical stimulation of the WP was recorded, and liposomal clodronate clophosome-A (LCCA; macrophage depletion agent) was administered to the TG at three and four days after pulp exposure. Immunohistochemically, TG sections were stained with anti-Iba1 (a macrophage marker) and anti-Nav1.7 antibodies. Pulp exposure decreased HWT and increased the number of Iba1-IR cells near FG-labelled TG neurons. LCCA inhibited the decrease in HWT and stopped the increase of FG-labelled Nav1.7-IR TG neurons in the pulpitis group. Activation of macrophages by pulpitis induces the overexpression of Nav1.7 in TG neurons receiving inputs from WP, resulting in pulpitis-induced ectopic facial mechanical allodynia. [ABSTRACT FROM AUTHOR] more...
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- 2024
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13. Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine.
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de Cássia Collaço, Rita, Lammens, Maxime, Blevins, Carley, Rodgers, Kristen, Gurau, Andrei, Yamauchi, Suguru, Kim, Christine, Forrester, Jeannine, Liu, Edward, Ha, Jinny, Mei, Yuping, Boehm, Corrine, Wohler, Elizabeth, Sobreira, Nara, Rowe, Peter C., Valle, David, Brock, Malcolm V., and Bosmans, Frank more...
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DYSAUTONOMIA , *HYPERHIDROSIS , *VAGAL tone , *ATTENTION-deficit hyperactivity disorder , *HYPERTENSION , *ANXIETY , *OFF-label use (Drugs) - Abstract
Purpose: Guanfacine is an α2A-adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility. Methods: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na+ channels were investigated using voltage-clamp electrophysiology. Results: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant NaV1.7 encoded by SCN9A, as well as other NaV channel subtypes to a varying degree. Conclusion: Our study provides further evidence for a possible pathophysiological role of NaV1.7 in anxiety and dysautonomia. Combined with off-target effects on NaV channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize NaV channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of NaV1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms. [ABSTRACT FROM AUTHOR] more...
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- 2024
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14. Therapeutic targeting of voltage-gated sodium channel NaV1.7 for cancer metastasis
- Author
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Piyasuda Pukkanasut, Renata Jaskula-Sztul, Juan Carlos Gomora, and Sadanandan E. Velu
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cancer ,metastasis ,voltage-gated sodium channel ,Nav1.7 ,therapeutic targeting ,cell invasion ,Therapeutics. Pharmacology ,RM1-950 - Abstract
This review focuses on the expression and function of voltage-gated sodium channel subtype NaV1.7 in various cancers and explores its impact on the metastasis driving cell functions such as proliferation, migration, and invasiveness. An overview of its structural characteristics, drug binding sites, inhibitors and their likely mechanisms of action are presented. Despite the lack of clarity on the precise mechanism by which NaV1.7 contributes to cancer progression and metastasis; many studies have suggested a connection between NaV1.7 and proteins involved in multiple signaling pathways such as PKA and EGF/EGFR-ERK1/2. Moreover, the functional activity of NaV1.7 appears to elevate the expression levels of MACC1 and NHE-1, which are controlled by p38 MAPK activity, HGF/c-MET signaling and c-Jun activity. This cascade potentially enhances the secretion of extracellular matrix proteases, such as MMPs which play critical roles in cell migration and invasion activities. Furthermore, the NaV1.7 activity may indirectly upregulate Rho GTPases Rac activity, which is critical for cytoskeleton reorganization, cell adhesion, and actin polymerization. The relationship between NaV1.7 and cancer progression has prompted researchers to investigate the therapeutic potential of targeting NaV1.7 using inhibitors. The positive outcome of such studies resulted in the discovery of several inhibitors with the ability to reduce cancer cell migration, invasion, and tumor growth underscoring the significance of NaV1.7 as a promising pharmacological target for attenuating cancer cell proliferation and metastasis. The research findings summarized in this review suggest that the regulation of NaV1.7 expression and function by small molecules and/or by genetic engineering is a viable approach to discover novel therapeutics for the prevention and treatment of metastasis of cancers with elevated NaV1.7 expression. more...
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- 2024
- Full Text
- View/download PDF
15. Role of voltage-gated sodium channels in axonal signal propagation of trigeminal ganglion neurons after infraorbital nerve entrapment
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Mulpuri, Yatendra, Yamamoto, Toru, Nishimura, Ichiro, and Spigelman, Igor
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Peripheral Neuropathy ,Pain Research ,Chronic Pain ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Neurological ,Axonal mRNA translation ,Axonal mRNA transport ,Axonal signal propagation ,Infraorbital nerve entrapment ,NaV1.3 ,NaV1.7 ,Nav1.8 ,Trigeminal neuropathy - Abstract
Chronic pain arising from peripheral nerve injuries represents a significant clinical challenge because even the most efficacious anticonvulsant drug treatments are limited by their side effects profile. We investigated pain behavior, changes in axonal signal conduction and excitability of trigeminal neurons, and expression of voltage-gated sodium channels (NaVs) in the infraorbital nerve and trigeminal ganglion (TG) after infraorbital nerve entrapment (IoNE). Compared to Sham, IoNE rats had increased A- and C-fiber compound action potentials (CAPs) and Aδ component of A-CAP area from fibers innervating the vibrissal pad. After IoNE, A- and C-fiber CAPs were more sensitive to blockade by tetrodotoxin (TTX), and those fibers that were TTX-resistant were more sensitive to blockade by the NaV1.8 selective blocker, A-803467. Although NaV1.7 blocker, ICA-121431 alone, did not affect Aδ-fiber signal propagation, cumulative application with A-803467 and 4,9-anhydro-TTX significantly reduced the Aδ-fiber CAP in IoNE rats. In patch clamp recordings from small- and medium-sized TG neurons, IoNE resulted in reduced action potential (AP) depolarizing current threshold, hyperpolarized AP voltage threshold, increased AP duration, and a more depolarized membrane potential. While the transcripts of most NaVs were reduced in the ipsilateral TG after IoNE, NaV1.3, NaV1.7, and NaV1.8 mRNAs, and NaV1.8 protein, were significantly increased in the nerve. Altogether, our data suggest that axonal redistribution of NaV1.8, and to a lesser extent NaV1.3, and NaV1.7 contributes to enhanced nociceptive signal propagation in peripheral nerve after IoNE. more...
- Published
- 2022
16. Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs
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Yu-Feng Xie, Jane Yang, Stéphanie Ratté, and Steven A Prescott
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pain ,degeneracy ,sodium channel ,Nav1.7 ,Nav1.8 ,excitability ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting NaV1.7 pharmacologically have struggled. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy – achieving similar function using different components – and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level. more...
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- 2024
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17. Differential expression of slow and fast-repriming tetrodotoxin-sensitive sodium currents in dorsal root ganglion neurons.
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Zhi-Yong Tan, Bin Wu, Xiaolin Su, You Zhou, and Yong-Hua Ji
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DORSAL root ganglia ,ACTION potentials ,NEURONS ,SODIUM channels ,SODIUM - Abstract
Sodium channel Nav1.7 triggers the generation of nociceptive action potentials and is important in sending pain signals under physiological and pathological conditions. However, studying endogenous Nav1.7 currents has been confounded by co-expression of multiple sodium channel isoforms in dorsal root ganglion (DRG) neurons. In the current study, slow-repriming (SR) and fast-repriming (FR) tetrodotoxin-sensitive (TTX-S) currents were dissected electrophysiologically in small DRG neurons of both rats and mice. Three subgroups of small DRG neurons were identified based on the expression pattern of SR and FR TTX-S currents. A majority of rat neurons only expressed SR TTX-S currents, while a majority of mouse neurons expressed additional FR TTX-S currents. ProTx-II inhibited SR TTX-S currents with variable efficacy among DRG neurons. The expression of both types of TTX-S currents was higher in Isolectin B4-negative (IB
4 − ) compared to Isolectin B4-positive (IB4 + ) neurons. Paclitaxel selectively increased SR TTX-S currents in IB4 − neurons. In simulation experiments, the Nav1.7-expressing small DRG neuron displayed lower rheobase and higher frequency of action potentials upon threshold current injections compared to Nav1.6. The results suggested a successful dissection of endogenous Nav1.7 currents through electrophysiological manipulation that may provide a useful way to study the functional expression and pharmacology of endogenous Nav1.7 channels in DRG neurons. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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18. Genetic, electrophysiological, and pathological studies on patients with SCN9A‐related pain disorders.
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Yuan, Jun‐Hui, Cheng, Xiaoyang, Matsuura, Eiji, Higuchi, Yujiro, Ando, Masahiro, Hashiguchi, Akihiro, Yoshimura, Akiko, Nakachi, Ryo, Mine, Jun, Taketani, Takeshi, Maeda, Kenichi, Kawakami, Saori, Kira, Ryutaro, Tanaka, Shoko, Kanai, Kazuaki, Dib‐Hajj, Fadia, Dib‐Hajj, Sulayman D., Waxman, Stephen G., and Takashima, Hiroshi more...
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PAIN , *PERIPHERAL neuropathy , *GENETICS , *ERYTHROMELALGIA , *GENETIC mutation , *GENETIC disorders , *ELECTROPHYSIOLOGY , *GENE expression profiling , *GENOMICS , *CASE studies , *RESEARCH funding , *PHENOTYPES , *FAMILY history (Medicine) - Abstract
Background and Aims: Voltage‐gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. Methods: We enrolled eight patients presenting with early‐onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM‐like disorders and two cases clinically diagnosed with PEPD. We conducted a gene‐panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP‐2A‐Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild‐type and F1624S Nav1.7 channels using an automated high‐throughput patch‐clamp system. Results: From two patients displaying EM‐like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch‐clamp analysis of Nav1.7‐F1624S revealed depolarizing shifts in both steady‐state fast inactivation (17.4 mV, p <.001) and slow inactivation (5.5 mV, p <.001), but no effect on channel activation was observed. Interpretation: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A‐related pain disorders, and the electrophysiological analysis enriches the understanding of genotype–phenotype association caused by Nav1.7 gain‐of‐function mutations. [ABSTRACT FROM AUTHOR] more...
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- 2023
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19. Neuropilin-1 is essential for vascular endothelial growth factor A–mediated increase of sensory neuron activity and development of painlike behaviors.
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Gomez, Kimberly, Duran, Paz, Tonello, Raquel, Allen, Heather N., Boinon, Lisa, Calderon-Rivera, Aida, Loya-López, Santiago, Nelsona, Tyler S., Ran, Dongzhi, Moutal, Aubin, Bunnett, Nigel W., and Khanna, Rajesh more...
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VASCULAR endothelial growth factors , *SENSORY neurons , *NEURON development , *DORSAL root ganglia , *NERVOUS system - Abstract
Neuropilin-1 (NRP-1) is a transmembrane glycoprotein that binds numerous ligands including vascular endothelial growth factor A (VEGFA). Binding of this ligand to NRP-1 and the co-receptor, the tyrosine kinase receptor VEGFR2, elicits nociceptor sensitization resulting in pain through the enhancement of the activity of voltage-gated sodium and calcium channels. We previously reported that blocking the interaction between VEGFA and NRP-1 with the Spike protein of SARS-CoV-2 attenuates VEGFA-induced dorsal root ganglion (DRG) neuronal excitability and alleviates neuropathic pain, pointing to the VEGFA/NRP-1 signaling as a novel therapeutic target of pain. Here, we investigated whether peripheral sensory neurons and spinal cord hyperexcitability and pain behaviors were affected by the loss of NRP-1. Nrp-1 is expressed in both peptidergic and nonpeptidergic sensory neurons. A CRIPSR/Cas9 strategy targeting the second exon of nrp-1 gene was used to knockdown NRP-1. Neuropilin-1 editing in DRG neurons reduced VEGFA-mediated increases in CaV2.2 currents and sodium currents through NaV1.7. Neuropilin-1 editing had no impact on voltage-gated potassium channels. Following in vivo editing of NRP-1, lumbar dorsal horn slices showed a decrease in the frequency of VEGFA-mediated increases in spontaneous excitatory postsynaptic currents. Finally, intrathecal injection of a lentivirus packaged with an NRP-1 guide RNA and Cas9 enzyme prevented spinal nerve injury–induced mechanical allodynia and thermal hyperalgesia in both male and female rats. Collectively, our findings highlight a key role of NRP-1 in modulating pain pathways in the sensory nervous system. [ABSTRACT FROM AUTHOR] more...
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- 2023
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20. Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain.
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Vasylyev, Dmytro V., Liu, Shujun, and Waxman, Stephen G.
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DORSAL root ganglia , *ACTION potentials , *HEART cells , *DRUG target , *GENETIC models - Abstract
We show here that hyperpolarization‐activated current (Ih) unexpectedly acts to inhibit the activity of dorsal root ganglion (DRG) neurons expressing WT Nav1.7, the largest inward current and primary driver of DRG neuronal firing, and hyperexcitable DRG neurons expressing a gain‐of‐function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain. In this study we created a kinetic model of Ih and used it, in combination with dynamic‐clamp, to study Ih function in DRG neurons. We show, for the first time, that Ih increases rheobase and reduces the firing probability in small DRG neurons, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih. Our results show that Ih, due to slow gating, is not deactivated during action potentials (APs) and has a striking damping action, which reverses from depolarizing to hyperpolarizing, close to the threshold for AP generation. Moreover, we show that Ih reverses the hyperexcitability of DRG neurons expressing a gain‐of‐function Nav1.7 mutation that causes IEM. In the aggregate, our results show that Ih unexpectedly has strikingly different effects in DRG neurons as compared to previously‐ and well‐studied cardiac cells. Within DRG neurons where Nav1.7 is present, Ih reduces depolarizing sodium current inflow due to enhancement of Nav1.7 channel fast inactivation and creates additional damping action by reversal of Ih direction from depolarizing to hyperpolarizing close to the threshold for AP generation. These actions of Ih limit the firing of DRG neurons expressing WT Nav1.7 and reverse the hyperexcitability of DRG neurons expressing a gain‐of‐function Nav1.7 mutation that causes IEM. Key points: Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, the molecular determinants of hyperpolarization‐activated current (Ih) have been characterized as a 'pain pacemaker', and thus considered to be a potential molecular target for pain therapeutics.Dorsal root ganglion (DRG) neurons express Nav1.7, a channel that is not present in central neurons or cardiac tissue. Gain‐of‐function mutations (GOF) of Nav1.7 identified in inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, produce DRG neuron hyperexcitability, which in turn produces severe pain.We found that Ih increases rheobase and reduces firing probability in small DRG neurons expressing WT Nav1.7, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih.We also demonstrate that Ih reverses the hyperexcitability of DRG neurons expressing a GOF Nav1.7 mutation (L858H) that causes IEM.Our results show that, in contrast to cardiac cells and CNS neurons, Ih acts to stabilize DRG neuron excitability and prevents excessive firing. [ABSTRACT FROM AUTHOR] more...
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- 2023
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21. A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials
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Dormer A, Narayanan M, Schentag J, Achinko D, Norman E, Kerrigan J, Jay G, and Heydorn W
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scn9a ,nav1.7 ,chronic pain ,opioid crisis ,Medicine (General) ,R5-920 - Abstract
Anton Dormer,1 Mahesh Narayanan,1 Jerome Schentag,1 Daniel Achinko,1 Elton Norman,1 James Kerrigan,2 Gary Jay,2 William Heydorn2 1Research and Development, Pepvax, Inc, Silver Spring, MD, USA; 2Research and Development, Navintus, Inc, Princeton, NJ, USACorrespondence: Anton Dormer, Research and Development, PepVax, Inc, 8720 Georgia Ave #1000, Silver Spring, MD, 20910, USA, Email anton.dormer@pepvax.coIntroduction: There is a great need to find alternative treatments for chronic pain which have become a healthcare problem. We discuss current therapeutic targeting Nav1.7.Areas Covered: Nav1.7 is a sodium ion channel protein that is associated with several human pain genetic syndromes. It has been found that mutations associated with Nav1.7 lead to the loss of the ability to perceive pain in individuals that are otherwise normal. Several therapeutic interventions are presently undergoing preclinical and research using the methodology of damping Nav1.7 expressions as a methodology to decrease the sensation of pain leading to analgesia.Expert Opinion: It is our strong belief that there is a viable future in the targeting of protein of Nav1.7 for the relief of chronic pain in humans. The review will look at the genomics associated with SCN1A and proteomic of Nav1.7 as a foundation to explain the mechanism of the therapeutic interventions targeting Nav1.7, the human disease that are associated with Nav1.7, and the current development of treatment for chronic pain whether in preclinical or clinical trials targeting Nav1.7 expressions. The development of therapeutic antagonists targeting Nav1.7 could be a viable alternative to the current treatments which have led to the opioid crisis. Therefore, Nav1.7 targeted treatment has a major clinical significance that will have positive consequences as it relates to chronic pain interventions.Keywords: SCN9A, Nav1.7, chronic pain, opioid crisis more...
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- 2023
22. Pathogenetic role of the pain threshold Hypothetical therapeutic perspectives based on the use of drugs to elevate it
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Guido Orlandini
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pain ,threshold. canalopathy ,nav1.7 ,ngf ,tanezumab ,Anesthesiology ,RD78.3-87.3 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The pain threshold determines the extent of pain perception, and in some cases, its manifestation. Therefore, it is important in certain situations to increase the pain threshold. Measuring the pain threshold is challenging due to its approximate nature. The threshold depends on the number and function of Nav1.7 sodium channels and nerve growth factor (NGF). Unfortunately, we lack therapeutic tools to selectively act on these sodium channels. The clinical use of tanezumab, a drug that can counteract NGF, has not been approved. It is potentially dangerous to misuse drugs that can increase the pain threshold as it may divert attention from treating the underlying cause of pain or even dangerously limit its protective function. However, they can be particularly useful in pathologies where the main pathogenetic mechanism is a reduced pain threshold, such as migraine, musculotensive headache, trigeminal neuropathy, phantom limb pain, fibromyalgia, and others. They are also helpful in situations where pain is no longer useful for diagnostic purposes and when it is due to an incurable condition like cancer. more...
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- 2023
23. Identification and targeting of a unique NaV1.7 domain driving chronic pain.
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Gomez, Kimberly, Stratton, Harrison J., Duran, Paz, Loya, Santiago, Cheng Tang, Calderon-Rivera, Aida, François-Moutal, Liberty, Khanna, May, Madura, Cynthia L., Luo, Shizhen, McKiver, Bryan, Choi, Edward, Dongzhi Ran, Boinon, Lisa, Perez-Miller, Samantha, Damaj, M. Imad, Moutal, Aubin, and Khanna, Rajesh more...
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CHRONIC pain , *GENE therapy , *NEURALGIA , *PEPTIDES , *RHESUS monkeys , *HYPNOTISM - Abstract
Small molecules directly targeting the voltage-gated sodium channel (VGSC) NaV1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other NaV isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased NaV1.7 currents. A cell-penetrant decoy peptide corresponding to the NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the NaV1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a NaV1.7 -targeted gene therapy, we packaged a plasmid encoding the NaV1.7-CRS in an AAV virus. Treatment with this virus reduced NaV1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy. These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain. [ABSTRACT FROM AUTHOR] more...
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- 2023
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24. Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in chronic constriction injury (CCI) rats
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Jiahe Li, Harrison J. Stratton, Sabina A. Lorca, Peter M. Grace, and Rajesh Khanna
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chronic pain ,nav1.7 ,crmp2 ,sumoylation ,nociceptor ,ubc9 ,Therapeutics. Pharmacology ,RM1-950 ,Physiology ,QP1-981 - Abstract
The voltage-gated sodium channel isoform NaV1.7 is a critical player in the transmission of nociceptive information. This channel has been heavily implicated in human genetic pain disorders and is a validated pain target. However, targeting this channel directly has failed, and an indirect approach – disruption of interactions with accessory protein partners – has emerged as a viable alternative strategy. We recently reported that a small-molecule inhibitor of CRMP2 SUMOylation, compound 194, selectively reduces NaV1.7 currents in DRG neurons across species from mouse to human. This compound also reversed mechanical allodynia in a spared nerve injury and chemotherapy-induced model of neuropathic pain. Here, we show that oral administration of 194 reverses mechanical allodynia in a chronic constriction injury (CCI) model of neuropathic pain. Furthermore, we show that orally administered 194 reverses the increased latency to cross an aversive barrier in a mechanical conflict-avoidance task following CCI. These two findings, in the context of our previous report, support the conclusion that 194 is a robust inhibitor of NaV1.7 function with the ultimate effect of profoundly ameliorating mechanical allodynia associated with nerve injury. The fact that this was observed using both traditional, evoked measures of pain behavior as well as the more recently developed operator-independent mechanical conflict-avoidance assay increases confidence in the efficacy of 194-induced anti-nociception. more...
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- 2022
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25. Targeting the vascular endothelial growth factor A/neuropilin 1 axis for relief of neuropathic pain.
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Stratton, Harrison J., Boinon, Lisa, Gomez, Kimberly, Martin, Laurent, Duran, Paz, Ran, Dongzhi, Zhou, Yuan, Luo, Shizhen, Perez-Miller, Samantha, Patek, Marcel, Ibrahim, Mohab M., Patwardhan, Amol, Moutal, Aubin, and Khanna, Rajesh more...
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VASCULAR endothelial growth factors , *NEURALGIA , *VOLTAGE-gated ion channels , *OPIOID receptors , *ENDOTHELIAL growth factors , *ANALGESIA , *SCIATIC nerve injuries - Abstract
Supplemental Digital Content is Available in the Text. NRP1-4 is a first-in-class compound uncoupling the neuropilin 1–vascular endothelial growth factor A signaling axis to reduce voltage-gated ion channel function, neuronal excitability, and synaptic activity that curbs chronic pain. Vascular endothelial growth factor A (VEGF-A) is a pronociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor neuropilin 1 (NRP1) and VEGF-A–blocked VEGF-A–mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. In an in-silico screening of approximately 480 K small molecules binding to the extracellular b1b2 pocket of NRP1, we identified 9 chemical series, with 6 compounds disrupting VEGF-A binding to NRP1. The small molecule with greatest efficacy, 4′-methyl-2′-morpholino-2-(phenylamino)-[4,5′-bipyrimidin]-6(1H)-one, designated NRP1-4, was selected for further evaluation. In cultured primary sensory neurons, VEGF-A enhanced excitability and decreased firing threshold, which was blocked by NRP1-4. In addition, NaV1.7 and CaV2.2 currents and membrane expression were potentiated by treatment with VEGF-A, and this potentiation was blocked by NRP1-4 cotreatment. Neuropilin 1-4 reduced VEGF-A–mediated increases in the frequency and amplitude of spontaneous excitatory postsynaptic currents in dorsal horn of the spinal cord. Neuropilin 1-4 did not bind to more than 300 G-protein-coupled receptors and receptors including human opioids receptors, indicating a favorable safety profile. In rats with spared nerve injury–induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation–induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, neuronal excitability, and synaptic activity that curb chronic pain. [ABSTRACT FROM AUTHOR] more...
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- 2023
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26. The β3‐subunit modulates the effect of venom peptides ProTx‐II and OD1 on NaV1.7 gating.
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Salvage, Samantha C., Rahman, Taufiq, Eagles, David A., Rees, Johanna S., King, Glenn F., Huang, Christopher L‐H., and Jackson, Antony P.
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SODIUM channels , *VENOM , *DORSAL root ganglia , *BINDING sites , *ALLOSTERIC regulation , *PEPTIDES - Abstract
The voltage‐gated sodium channel NaV1.7 is involved in various pain phenotypes and is physiologically regulated by the NaV‐β3‐subunit. Venom toxins ProTx‐II and OD1 modulate NaV1.7 channel function and may be useful as therapeutic agents and/or research tools. Here, we use patch‐clamp recordings to investigate how the β3‐subunit can influence and modulate the toxin‐mediated effects on NaV1.7 function, and we propose a putative binding mode of OD1 on NaV1.7 to rationalise its activating effects. The inhibitor ProTx‐II slowed the rate of NaV1.7 activation, whilst the activator OD1 reduced the rate of fast inactivation and accelerated recovery from inactivation. The β3‐subunit partially abrogated these effects. OD1 induced a hyperpolarising shift in the V1/2 of steady‐state activation, which was not observed in the presence of β3. Consequently, OD1‐treated NaV1.7 exhibited an enhanced window current compared with OD1‐treated NaV1.7‐β3 complex. We identify candidate OD1 residues that are likely to prevent the upward movement of the DIV S4 helix and thus impede fast inactivation. The binding sites for each of the toxins and the predicted location of the β3‐subunit on the NaV1.7 channel are distinct. Therefore, we infer that the β3‐subunit influences the interaction of toxins with NaV1.7 via indirect allosteric mechanisms. The enhanced window current shown by OD1‐treated NaV1.7 compared with OD1‐treated NaV1.7‐β3 is discussed in the context of differing cellular expressions of NaV1.7 and the β3‐subunit in dorsal root ganglion (DRG) neurons. We propose that β3, as the native binding partner for NaV1.7 in DRG neurons, should be included during screening of molecules against NaV1.7 in relevant analgesic discovery campaigns. [ABSTRACT FROM AUTHOR] more...
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- 2023
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27. Voltage-Gated Sodium Channel Na V 1.7 Inhibitors with Potent Anticancer Activities in Medullary Thyroid Cancer Cells.
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Pukkanasut, Piyasuda, Whitt, Jason, Guenter, Rachael, Lynch, Shannon E., Gallegos, Carlos, Rosendo-Pineda, Margarita Jacaranda, Gomora, Juan Carlos, Chen, Herbert, Lin, Diana, Sorace, Anna, Jaskula-Sztul, Renata, and Velu, Sadanandan E. more...
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THERAPEUTIC use of antineoplastic agents , *TISSUE arrays , *CANCER cells , *SODIUM channel blockers , *THYROID gland tumors , *WESTERN immunoblotting , *IMMUNOHISTOCHEMISTRY , *CANCER invasiveness , *GENE expression , *CANCER patients , *CELL survival , *CELL proliferation , *CELL migration inhibition , *RESEARCH funding , *MEMBRANE proteins , *TUMOR markers , *POLYMERASE chain reaction , *PHARMACODYNAMICS , *CHEMICAL inhibitors - Abstract
Simple Summary: Despite the recent advances in the diagnosis and treatment of medullary thyroid cancer (MTC), it remains an understudied cancer type and continues to disproportionately contribute to thyroid-cancer-related mortality. In this manuscript, we report, for the first time, the overexpression of voltage-gated sodium channel subtype NaV1.7 in MTC cells and MTC patient samples, which is not expressed in normal thyroid cells and tissues. We establish the druggability of this channel by identifying a novel inhibitor (SV188) of this channel and investigate its mode of binding and ability to inhibit the INa current in NaV1.7. We also show that SV188 significantly inhibited the migration and invasion of aggressive MTC cells at doses lower than its cytotoxic concentration. Overall, our data suggest that the unique overexpression of NaV1.7 in MTC can be exploited for the discovery of novel small-molecule drugs to treat MTC metastasis. Our results from quantitative RT-PCR, Western blotting, immunohistochemistry, and the tissue microarray of medullary thyroid cancer (MTC) cell lines and patient specimens confirm that VGSC subtype NaV1.7 is uniquely expressed in aggressive MTC and not expressed in normal thyroid cells and tissues. We establish the druggability of NaV1.7 in MTC by identifying a novel inhibitor (SV188) and investigate its mode of binding and ability to inhibit INa current in NaV1.7. The whole-cell patch-clamp studies of the SV188 in the NaV1.7 channels expressed in HEK-293 cells show that SV188 inhibited the INa current in NaV1.7 with an IC50 value of 3.6 µM by a voltage- and use-dependent blockade mechanism, and the maximum inhibitory effect is observed when the channel is open. SV188 inhibited the viability of MTC cell lines, MZ-CRC-1 and TT, with IC50 values of 8.47 μM and 9.32 μM, respectively, and significantly inhibited the invasion of MZ-CRC-1 cells by 35% and 52% at 3 μM and 6 μM, respectively. In contrast, SV188 had no effect on the invasion of TT cells derived from primary tumor, which have lower basal expression of NaV1.7. In addition, SV188 at 3 μM significantly inhibited the migration of MZ-CRC-1 and TT cells by 27% and 57%, respectively. [ABSTRACT FROM AUTHOR] more...
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- 2023
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28. 一种来源于蜘蛛毒液的新型Nav1.7 多肽抑制剂的 发现与鉴定.
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罗 森, 杨 坤, 李 闽, 肖文萱, 雷 伟, 张紫萱, and 陈敏芝
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Voltage-gated sodium channel Nav1.7 is preferentially expressed in peripheral nociceptors. Clinical genetics, animal models and pharmacological studies indicate that Nav1.7 is an important target for analgesic drug development. In this paper, we report the isolation and characterization of APTX-1, a novel peptide toxin from the venom of spider Calommata signata Karsch. Patch-clamp analysis confirmed that APTX-1 potently inhibits the currents of Nav1.7. Mass spectrum results showed that the molecular weight of APTX-1 was 7 815.2 Da. The first 10 amino acid positions at the N terminal were ASCKQVGEEC. APTX-1 inhibited Nav1.7 currents in a concentration-dependent manner, with a half-inhibitory concentration of (0.46±0.08) μmol/L. Channel dynamics analysis showed that APTX-1 did not affect the reversal potential, voltage-dependent steady-state activation curve, and inactivation curve of Nav1.7, indicating that the peptide toxin did not affect the ion selectivity and voltage dependence of Nav1.7. In conclusion, we found a novel Nav1.7 peptide inhibitor, and the characteristics of its action on Nav1.7 were studied to provide lead molecules for the development of analgesic drugs targeting the Nav1.7. [ABSTRACT FROM AUTHOR] more...
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- 2023
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29. Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model.
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Yan Fu, Liting Sun, Fengting Zhu, Wei Xia, Ting Wen, Ruilong Xia, Xin Yu, Dan Xu, and Changgeng Peng
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NEURALGIA ,DORSAL root ganglia ,NEURONS ,NEUROTROPHIN receptors ,MICE - Abstract
Neuropathic pain (NP) induced by spinal cord injury (SCI) often causes long-term disturbance for patients, but the mechanisms behind remains unclear. Here, our study showed SCI-induced ectopic expression of Nav1.7 in abundant neurons located in deep and superficial laminae layers of the spinal dorsal horn (SDH) and upregulation of Nav1.7 expression in dorsal root ganglion (DRG) neurons in mice. Pharmacologic studies demonstrated that the efficacy of the blood-brain-barrier (BBB) permeable Nav1.7 inhibitor GNE-0439 for attenuation of NP in SCI mice was significantly better than that of the BBB non-permeable Nav1.7 inhibitor PF-05089771. Moreover, more than 20% of Nav1.7-expressing SDH neurons in SCI mice were activated to express FOS when there were no external stimuli, suggesting that the ectopic expression of Nav1.7 made SDH neurons hypersensitive and Nav1.7-expressing SDH neurons participated in central sensitization and in spontaneous pain and/or walking-evoked mechanical pain. Further investigation showed that NGF, a strong activator of Nav1.7 expression, and its downstream JUN were upregulated after SCI in SDH neurons with similar distribution patterns and in DRG neurons too. In conclusion, our findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF/JUN, and the inhibition of Nav1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice. These data suggest that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI via selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP. [ABSTRACT FROM AUTHOR] more...
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- 2023
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30. Naked Mole-Rats Demonstrate Profound Tolerance to Low Oxygen, High Carbon Dioxide, and Chemical Pain.
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Amoroso, Vince G., Zhao, Aishi, Vargas, Isabel, and Park, Thomas J.
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ATMOSPHERIC carbon dioxide , *CARBON dioxide , *NAKED mole rat , *ENERGY conservation , *ANAEROBIC metabolism - Abstract
Simple Summary: Naked mole-rats live in crowded underground burrows where concentrations of oxygen can be low and concentrations of carbon dioxide can be high. Accordingly, this species is tolerant of low oxygen levels and high carbon dioxide levels, which would be deadly to most surface dwellers. The current article reviews what we know about these unusual tolerances and their underlying mechanisms. Understanding these mechanisms could lead to new strategies for treating human disorders related to low oxygen and high carbon dioxide, as experienced, for example, during a heart attack. Naked mole-rats (Heterocephalus glaber) are very unusual among subterranean mammals in that they live in large colonies and are extremely social, spending large amounts of time gathered together in underground nests more than a meter below the surface. Many respiring individuals resting in deep, poorly ventilated nests deplete the oxygen supply and increase the concentration of carbon dioxide. Consistent with living in that atmosphere, naked mole-rats tolerate levels of low oxygen and high carbon dioxide that are deadly to most surface-dwelling mammals. Naked mole-rats appear to have evolved a number of remarkable adaptations to be able to thrive in this harsh atmosphere. In order to successfully survive low oxygen atmospheres, they conserve energy utilization by reducing the physiological activity of all organs, manifest by reduced heart rate and brain activity. Amazingly, they resort to the anaerobic metabolism of fructose rather than glucose as a fuel to generate energy when challenged by anoxia. Similarly, high carbon dioxide atmospheres normally cause tissue acidosis, while naked mole-rats have a genetic mutation preventing both acid-induced pain and pulmonary edema. Together, these putative adaptations and the tolerances they provide make the naked mole-rat an important model for studying a host of biomedical challenges. [ABSTRACT FROM AUTHOR] more...
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- 2023
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31. Nav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons.
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Ghovanloo, Mohammad-Reza, Effraim, Philip R., Jun-Hui Yuan, Schulman, Betsy R., Jacobs, Deborah S., Dib-Hajj, Sulayman D., and Waxman, Stephen G.
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EYE pain , *CHRONIC pain , *AXONS , *NEURONS , *LASIK , *CORNEAL dystrophies - Abstract
Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser-assisted in situ keratomileusis (LASIK). Although most patients do not experience postoperative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons, the ensemble of ion channels and receptors that regulate excitability within these cells, including SCN9A, which encodes sodium channel Nav1.7, a threshold channel abundantly expressed in sensory neurons that has been implicated in a number of pain-related disorders. Here, we describe the biophysical and electrophysiological profiling of the P610T Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery. Our results indicate that this mutation impairs the slow inactivation of Nav1.7. As expected from this proexcitatory change in channel function, we also demonstrate that this mutation produces increased spontaneous activity in trigeminal ganglion neurons. These findings suggest that this gain-of-function mutation in Nav1.7 may contribute to pain after injury to the axons of trigeminal ganglion neurons. [ABSTRACT FROM AUTHOR] more...
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- 2023
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32. 20S-Ginsenoside Rh2, the major bioactive saponin in Panax notoginseng flowers, ameliorates cough by inhibition of NaV1.7 and TRPV1 channel currents and downregulation of TRPV1 expression.
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Liu, Xiao, Xiang, Jie, Fan, Shuyuan, Chen, Xumin, Peng, Chengzhan, and Xu, Zhengxin
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CHINESE medicine , *HIGH performance liquid chromatography , *GUINEA pigs , *CYTOLOGY , *COMPUTER-assisted molecular modeling , *CARRIER proteins , *LIQUID chromatography-mass spectrometry , *FLOWERS , *PLANT extracts , *NERVE tissue proteins , *GENE expression , *MICE , *IMMUNOHISTOCHEMISTRY , *GLYCOSIDES , *WATER , *ANIMAL experimentation , *WESTERN immunoblotting , *GINSENG , *COUGH , *ORGANIC compounds , *STAINS & staining (Microscopy) , *ANTITUSSIVE agents , *PHARMACODYNAMICS , *CHEMICAL inhibitors - Abstract
Panax notoginseng flowers, which are the buds of the traditional Chinese medicinal herb Sanqi, are widely used in China for their cough-ameliorating properties, with demonstrated therapeutic effects in the treatment of both acute and chronic coughs. However, both the antitussive mechanism and active compound basis of P. notoginseng flowers remain poorly understood. We investigated the antitussive effects of P. notoginseng flowers, identified the bioactive constituents responsible for alleviating cough symptoms, and elucidated the underlying pharmacological mechanisms. We analyzed the major chemical constituents of aqueous extracts of P. notoginseng flowers using liquid chromatography–mass spectrometry and quantitatively analyzed the key component, 20S-ginsenoside Rh2, using high-performance liquid chromatography. Using a cough reflex model in healthy mice and an ovalbumin-induced, highly sensitive guinea pig cough model, we verified the suppressive effects of P. notoginseng flowers and their saponin constituents on coughing. Furthermore, we explored the mechanisms of action of the key ion channels, NaV1.7 and TRPV1, using whole-cell patch-clamp techniques and molecular docking. Finally, the therapeutic mechanisms of P. notoginseng flowers on pathological cough were revealed using hematoxylin and eosin staining, immunohistochemistry, and western blotting. The active components of P. notoginseng flowers were primarily protopanaxadiol-type saponins, among which 20S-ginsenoside Rh2 had the highest content (51.46 mg/g). In the mouse model, P. notoginseng flowers exhibited antitussive effects comparable to those of pentoxyverine citrate. Although its main saponin component, 20S-ginsenoside Rh2, showed slightly weaker effects, it still demonstrated concentration-dependent inhibition of channel activity. The whole-cell patch-clamp technique and virtual molecular docking showed that Rh2 might exert its effects by directly binding to the NaV1.7 and TRPV1 channels. In the guinea pig model, P. notoginseng flowers and their saponin components not only reduced cough frequency and prolonged the latency period before cough onset, but also significantly inhibited tracheal and pulmonary inflammation and the overexpression of TRPV1. 20S-Ginsenoside Rh2, the major bioactive saponin in P. notoginseng flowers, exhibits potent antitussive effects. The potential mechanism of action of 20S-Ginsenoside Rh2 in the treatment of cough may involve inhibiting NaV1.7 and TRPV1 channel currents through direct binding to core protein active sites and downregulating TRPV1 expression. [Display omitted] • 20S-ginsenoside Rh2 can ameliorate cough. • 20S-ginsenoside Rh2 inhibits NaV1.7 and TRPV1 channel currents. • 20S-ginsenoside Rh2 also reduces cough sensitivity by decreasing TRPV1 overexpression. [ABSTRACT FROM AUTHOR] more...
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- 2025
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33. Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.
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Alsaloum, Matthew, Labau, Julie I R, Liu, Shujun, Effraim, Philip R, and Waxman, Stephen G
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SENSORY neurons , *DRUG discovery , *GAIN-of-function mutations , *PAIN management , *THERAPEUTICS - Abstract
Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels. [ABSTRACT FROM AUTHOR] more...
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- 2023
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34. Polysorbate 80 blocked a peripheral sodium channel, Nav1.7, and reduced neuronal excitability.
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Ryeong-Eun Kim and Jin-Sung Choi
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POLYSORBATE 80 , *SODIUM channels , *DORSAL root ganglia , *ACTION potentials , *SENSORY neurons - Abstract
Polysorbate 80 is a non-ionic detergent derived from polyethoxylated sorbitan and oleic acid. It is widely used in pharmaceuticals, foods, and cosmetics as an emulsifier. Nav1.7 is a peripheral sodium channel that is highly expressed in sympathetic and sensory neurons, and it plays a critical role in determining the threshold of action potentials (APs). We found that 10 µg/mL polysorbate 80 either abolished APs or increased the threshold of the APs of dorsal root ganglions. We thus investigated whether polysorbate 80 inhibits Nav1.7 sodium current using a whole-cell patch-clamp recording technique. Polysorbate 80 decreased the Nav1.7 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 250.4 µg/mL at a holding potential of -120 mV. However, the IC50 was 1.1 µg/mL at a holding potential of -90 mV and was estimated to be 0.9 µg/mL at the resting potentials of neurons, where most channels are inactivated. The activation rate and the voltage dependency of activation of Nav1.7 were not changed by polysorbate 80. However, polysorbate 80 caused hyperpolarizing shifts in the voltage dependency of the steady-state fast inactivation curve. The blocking of Nav1.7 currents by polysorbate 80 was not reversible at a holding potential of -90 mV but was completely reversible at -120 mV, where the channels were mostly in the closed state. Polysorbate 80 also slowed recovery from inactivation and induced robust usedependent inhibition, indicating that it is likely to bind to and stabilize the inactivated state. Our results indicate that polysorbate 80 inhibits Nav1.7 current in concentration-, state-, and use-dependent manners when used even below commercial concentrations. This suggests that polysorbate 80 may be helpful in pain medicine as an excipient. In addition, in vitro experiments using polysorbate 80 with neurons should be conducted with caution. [ABSTRACT FROM AUTHOR] more...
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- 2023
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35. Nav1.7、Nav1.8 和交感芽生在大鼠 SNI 模型神经 病理性疼痛形成过程中的作用.
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李笑笑, 陈 涵, 李妍妍, 朱玉静, 张 谭, and 唐 俊
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Objective To investigate the relationship between Nav1.7, Nav1.8 and sympathetic sprouting in dorsal root ganglion (DRG) during neuropathic pain induced by spared nerve injury (SNI). Methods The experimental rats were randomly divided into Control group (n=18) and SNI group (n= 18). Mechanical withdrawal threshold (MWT) was measured on the 3rd, 7th, 14th and 21st days after surgery. The mRNA expressions and protein contents of Nav1.7, Nav1.8, growth-associated protein 43 (GAP43) and tyrosine hydroxylase (TH) were detected respectively from operative side lumbar DRGs which were extracted on the 7th and 21st days, and immunofluorescence staining were performed concurrently. Results Compared with Control group, MWT in SNI group was reduced time-dependently. On the 7th day and 21st day in the SNI group, mRNA expressions and protein contents of Nav1.7 and Nav1.8 in the DRGs increased synchronously with the mRNA expand protein contents of GAP43 and TH. Immunofluorescence staining showed that large-diameter neurons which expressed Nav1.7, Nav1.8 and GAP43 abnormally increased on the postoperative 21st day. Especially, the positive neurons of Nav1.7 and Nav1.8 respectively were surrounded by TH positive fibers which formed basketlike structures. Conclusion Sympathetic sprouting and basket structure on the medium and large neurons in DRG after sciatic nerve injury were related to the synchronous increasing of Nav1.7 and Nav1.8. This phenomenon may be one of the formation factors of neuropathic pain. [ABSTRACT FROM AUTHOR] more...
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- 2023
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36. Polygodial, a drimane sesquiterpenoid dialdehyde purified from Drimys winteri, inhibits voltage-gated sodium channels.
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Paz, Cristian, Ortiz, Leandro, Deuis, Jennifer R., and Vetter, Irina
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SODIUM channels ,TRP channels ,MAPUCHE (South American people) ,NUCLEAR magnetic resonance ,VOLTAGE-gated ion channels ,VIMPAT - Abstract
Drimys winteri J.R.Forst. & G.Forst, a South American evergreen shrub that is used by the Mapuche people for treatment of several painful conditions, contains polygodial, a lipophilic drimane-type sesquiterpene dialdehyde with known activity at transient receptor potential channel family members including TRPA1 and TRPV1. We sought to assess the activity of polygodial at Na
V 1.7 and NaV 1.8, two key isoforms of the voltage-gated sodium channel family involved in nociception. Polygodial was isolated from D. winteri by thin-layer chromatography and analysed structurally by 1 D and 2 D nuclear magnetic resonance (NMR) spectroscopy. Activity at heterologously expressed NaV 1.7 and NaV 1.8 was assessed using automated whole-cell patch-clamp electrophysiology. Here, we show that polygodial inhibits members of the voltage-gated sodium channel family, specifically NaV 1.7 and NaV 1.8, without changing the voltage-dependence of activation or inactivation. Activity of polygodial at voltage-gated sodium channels may contribute to the previously reported antinociceptive properties. [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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37. Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Na v 1.7 Voltage-Gated Sodium Channel.
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Yang, Haoyi, Shan, Zhiming, Guo, Weijie, Wang, Yuwei, Cai, Shuxian, Li, Fuyi, Huang, Qiaojie, Liu, Jessica Aijia, Cheung, Chi Wai, and Cai, Song
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SODIUM channels , *NEURALGIA , *SENSORY neurons , *NATURAL products , *NOCICEPTORS , *CALCITONIN gene-related peptide , *DORSAL root ganglia , *DRUG target - Abstract
Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the Citrus unshiu, showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin's antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (NaV) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) NaV channels, and (iv) blunts the upregulation of Nav1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Nav1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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38. Multifactorial pathways in burn injury-induced chronic pain: novel targets and their pharmacological modulation.
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Roy, Tapas Kumar, Uniyal, Ankit, ., Akhilesh, and Tiwari, Vinod
- Abstract
Burn injuries are among the highly prevalent medical conditions worldwide that occur mainly in children, military veterans and victims of fire accidents. It is one of the leading causes of temporary as well as permanent disabilities in patients. Burn injuries are accompanied by pain that persists even after recovery from tissue damage which puts immense pressure on the healthcare system. The pathophysiology of burn pain is poorly understood due to its complex nature and lack of considerable preclinical and clinical shreds of evidence, that creates a substantial barrier to the development of new analgesics. Burns damage the skin layers supplied with nociceptors such as NAV1.7, TRPV1, and TRPA1. Burn injury-mediated co-localization and simultaneous activation of TRPA1 and TRPV1 in nociceptive primary afferent C-fibers which contributes to the development and maintenance of chronic pain. Burn injuries are accompanied by central sensitization, a key feature of pain pathophysiology mainly driven by a series of cascades involving aberrations in the glutamatergic system, microglial activation, release of neuropeptides, cytokines, and chemokines. Activation of p38 mitogen-activated protein kinase, altered endogenous opioid signaling, and distorted genomic expression are other pathophysiological factors responsible for the development and maintenance of burn pain. Here we discuss comprehensive literature on molecular mechanisms of burn pain and potential targets that could be translated into near future therapeutics. [ABSTRACT FROM AUTHOR] more...
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- 2022
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39. [ Tougu Xiaotong Capsule alleviates cartilage degeneration in mice with knee osteoarthritis by modulating Nav1.7].
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Fu C, Lin Y, Lan S, Chen Y, Li C, Lu S, and Lin Q
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- Animals, Mice, Disease Models, Animal, Matrix Metalloproteinase 3 metabolism, ADAMTS5 Protein metabolism, ADAMTS5 Protein genetics, Cartilage, Articular metabolism, Cartilage, Articular drug effects, Cartilage, Articular pathology, Osteoarthritis, Knee drug therapy, Osteoarthritis, Knee metabolism, Mice, Inbred C57BL, Chondrocytes metabolism, Chondrocytes drug effects, Drugs, Chinese Herbal pharmacology, Drugs, Chinese Herbal therapeutic use, Cyclooxygenase 2 metabolism, NAV1.7 Voltage-Gated Sodium Channel metabolism, NAV1.7 Voltage-Gated Sodium Channel genetics
- Abstract
Objective: To investigate the mechanism by which Tougu Xiaotong Capsule (TGXTC) alleviates chondrocyte degeneration in knee osteoarthritis (KOA)., Methods: Thirty 2-month-old C57BL/6 mouse models of KOA established using the Hulth method were randomized into model group, TGXTC group, and diclofenac sodium group and received treatment with saline, TGXTC (368 mg/kg), and diclofenac sodium (10 mg/kg) by gavage, respectively, with another 10 untreated mice as the blank control group. All interventions were administered 6 times a week for 4 weeks. After the treatments, structural changes in the cartilage tissue were observed with morphological staining, and Nav1.7 mRNA expression and the protein expression levels of Nav1.7, MMP-3, ADAMTS-5, and COX-2 were detected using RT-qPCR and Western blotting. Fluorescence in situ hybridization (FISH) was used to detect Nav1.7 expression in the chondrocytes. In cultured KOA chondrocytes, the effect of TGXTC and lentivirus-mediated Nav1.7 knockdown on MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, and COX-2 protein expressions were assessed with Western blotting., Results: In KOA mice treatments with TGXTC and diclofenac sodium both significantly alleviated structural damage of the cartilage layer, reduced Nav1.7 protein and mRNA expressions and lowered the expressions of MMP-3, ADAMTS-5, and COX-2 proteins in the cartilage tissues. FISH results indicated that TGXTC treatment significantly reduced IL-1β -induced Nav1.7 expression in the chondrocytes. In Nav1.7 knockdown experiment, Nav1.7 levels were significantly lower in IL-1β+sh-Nav1.7 group than in IL-1β group, and also lower in IL-1β+TGXTC group than in IL-1β+sh-Nav1.7+TGXTC group. TGXTC treatment significantly inhibited IL-1β-induced elevation of MMP-3, MMP-13, ADAMTS-4, ADAMTS-5 and COX-2 protein expressions in the chondrocytes, but its effects were strongly weakened by Nav1.7 knockdown., Conclusion: TGXTC alleviates extracellular matrix metabolic disorder in KOA chondrocytes by regulating Nav1.7, thereby mitigating chondrocyte degeneration in KOA mice. more...
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- 2024
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40. Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.
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Middleton, Steven J, Perini, Irene, Themistocleous, Andreas C, Weir, Greg A, McCann, Kirsty, Barry, Allison M, Marshall, Andrew, Lee, Michael, Mayo, Leah M, Bohic, Manon, Baskozos, Georgios, Morrison, India, Löken, Line S, McIntyre, Sarah, Nagi, Saad S, Staud, Roland, Sehlstedt, Isac, Johnson, Richard D, Wessberg, Johan, and Wood, John N more...
- Abstract
Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch. [ABSTRACT FROM AUTHOR] more...
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- 2022
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41. Lidocaine reduces pain behaviors by inhibiting the expression of Nav1.7 and Nav1.8 and diminishing sympathetic sprouting in SNI rats.
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Li, Xiaoxiao, Chen, Han, Zhu, Yujing, Li, Yanyan, Zhang, Tan, and Tang, Jun
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DORSAL root ganglia , *GERMINATION , *SYMPATHETIC nervous system , *LIDOCAINE , *NEURALGIA - Abstract
Chronic neuropathic pain is a significant clinical challenge, and the mechanisms of neuropathic pain remain elusive. Previous studies have shown that spontaneous potential, which is triggered by Nav1.7 and Nav1.8 in the dorsal root ganglion (DRG), is crucial for the development of inflammatory and neuropathic pain. Functional coupling between the sympathetic nervous system and somatosensory nerves after a nerve injury has also been noted as an important factor in neuropathic pain. However, the relationship of sympathetic sprouting with Nav1.7 and Nav1.8 remains unclear. Therefore, we dynamically examined the mechanical withdrawal threshold (MWT), changes in Nav1.7 and Nav1.8, and sympathetic sprouting after lidocaine treatment in the spared nerve injury (SNI) model of rats. After lidocaine treatment, the MWT obviously increased, showing that hypersensitivity was significantly relieved and the abnormal expression of Nav1.7 and Nav1.8 caused by SNI was also significantly reduced. In addition, lidocaine distinctly inhibited sympathetic nerve sprouting and basket formation around the Nav1.7 and Nav1.8 neurons in the DRG. These results indicate that lidocaine may alleviate neuropathic pain by inhibiting the expression of Nav1.7 and Nav1.8, and diminishing sympathetic sprouting in DRG. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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42. Prediction and verification of potential lead analgesic and antiarrhythmic components in Corydalis yanhusuo W. T. Wang based on voltage-gated sodium channel proteins.
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Sun, Jianfang, Liu, Xin, Zhao, Shangfeng, Zhang, Suli, Yang, Liying, Zhang, Jinghai, Zhao, Mingyi, and Xu, Yijia
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CONOTOXINS , *SODIUM channels , *CORYDALIS , *CHINESE medicine , *MEDICAL databases , *ION channels , *BLOOD circulation - Abstract
Corydalis yanhusuo W. T. Wang, a traditional Chinese herbal medicine, has been used as an analgesic for thousands of years and it also promotes blood circulation. In this study, 33 Corydalis yanhusuo alkaloid active components were acquired from Traditional Chinese Medicine Database and Analysis Platform (TCMSP). A total of 543 pain-related targets, 1774 arrhythmia targets, and 642 potential targets of these active components were obtained using Swiss Target Prediction, GeneCards, Open Target Platform, and Therapeutic Target Database. Fifty intersecting targets were visualized through a Venn diagram, KEGG and GO pathway enrichment analysis. The analysis proposed that sodium ion channels are likely potential targets of Corydalis yanhusuo active components as analgesia and anti-arrhythmia agents. Molecular docking showed that the 33 components could bind to Nav1.7 and Nav1.5 (two subtypes of ion channel proteins) with different binding energies. In a patch clamp study, dihydrosanguinarine and dihydrochelerythrine, two monomers with the strongest binding effects, could inhibit the peak currents and promote both activation and inactivation phases of Nav1.5. Meanwhile, dihydrosanguinarine and dihydrochelerythrine could also inhibit peak currents and promote the activation phase of Nav1.7. Therefore, the findings from this study provide valuable information for future uses of traditional Chinese medicines to treat pain and cardiovascular disease. [ABSTRACT FROM AUTHOR] more...
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- 2022
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43. Functional expression of NaV1.7 channels in freshly dispersed mouse bronchial smooth muscle cells.
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Matthews, Ruth M., Bradley, Eamonn, Griffin, Caoimhin S., Xin Rui Lim, Mullins, Nicolas D., Hollywood, Mark A., Lundy, Fionnuala T., McGarvey, Lorcan P., Sergeant, Gerard P., and Thornbury, Keith D.
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SMOOTH muscle , *MUSCLE cells , *SODIUM channels , *TETRODOTOXIN , *ATROPINE , *BRONCHI - Abstract
Isolated smooth muscle cells (SMCs) from mouse bronchus were studied using the whole cell patch-clamp technique at ~21°C. Stepping from -100 mV to -20 mV evoked inward currents of mean amplitude -275 pA. These inactivated (tau = 1.1 ms) and were abolished when external Na+ was substituted with N-Methyl-D-glucamine. In current-voltage protocols, current peaked at -10 mV and reversed between + 20 and + 30 mV. The V1/2s of activation and inactivation were -25 and -86 mV, respectively. The current was highly sensitive to tetrodotoxin (IC50 = 1.5 nM) and the NaV1.7 subtype-selective blocker, PF-05089771 (IC50 = 8.6 nM), consistent with NaV1.7 as the underlying pore-forming α subunit. Two NaV1.7-selective antibodies caused membrane- delineated staining of isolated SMC, as did a nonselective pan-NaV antibody. RT-PCR, performed on groups of ~15 isolated SMCs, revealed transcripts for NaV1.7 in 7/8 samples. Veratridine (30 µM), a nonselective NaV channel activator, reduced peak current evoked by depolarization but induced a sustained current of 40 pA. Both effects were reversed by tetrodotoxin (100 nM). In tension experiments, veratridine (10 µM) induced contractions that were entirely blocked by atropine (1 µM). However, in the presence of atropine, veratridine was able to modulate the pattern of activity induced by a combination of U-46619 (a thromboxane A2 mimetic) and PGE2 (prostaglandin E2), by eliminating bursts in favor of sustained phasic contractions. These effects were readily reversed to control-like activity by tetrodotoxin (100 nM). In conclusion, mouse bronchial SMCs functionally express NaV1.7 channels that are capable of modulating contractile activity, at least under experimental conditions. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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44. General mechanism of spider toxin family I acting on sodium channel Nav1.7.
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Fu-Chu Yuan, Fu-De Sun, Lin Zhang, Biao Huang, Hai-Long An, Ming-Qiang Rong, and Can-Wei Du
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SPIDER venom ,SODIUM channels ,VOLTAGE-gated ion channels ,TOXINS ,PEPTIDES ,SPIDERS - Abstract
Various peptide toxins in animal venom inhibit voltage-gated sodium ion channel Nav1.7, including Nav-targeting spider toxin (NaSpTx) Family I. Toxins in NaSpTx Family I share a similar structure, i.e., N-terminal, loops 1–4, and C-terminal. Here, we used Mu-theraphotoxin-Ca2a (Ca2a), a peptide isolated from Cyriopagopus albostriatus, as a template to investigate the general properties of toxins in NaSpTx Family I. The toxins interacted with the cell membrane prior to binding to Nav1.7 via similar hydrophobic residues. Residues in loop 1, loop 4, and the C-terminal primarily interacted with the S3–S4 linker of domain II, especially basic amino acids binding to E818. We also identified the critical role of loop 2 in Ca2a regarding its affinity to Nav1.7. Our results provide further evidence that NaSpTx Family I toxins share similar structures and mechanisms of binding to Nav1.7. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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45. There is no F in APC: Using physiological fluoride-free solutions for high throughput automated patch clamp experiments.
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Rapedius, Markus, Obergrussberger, Alison, Humphries, Edward S. A., Scholz, Stephanie, Rinke-Weiss, Ilka, Goetze, Tom A., Brinkwirth, Nina, Rotordam, Maria Giustina, Strassmaier, Tim, Randolph, Aaron, Friis, Søren, Liutkute, Aiste, Seibertz, Fitzwilliam, Voigt, Niels, and Fertig, Niels more...
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CHO cell ,VOLTAGE control ,FLUORIDES ,ION channels ,UMBILICAL cord clamping - Abstract
Fluoride has been used in the internal recording solution for manual and automated patch clamp experiments for decades because it helps to improve the seal resistance and promotes longer lasting recordings. In manual patch clamp, fluoride has been used to record voltage-gated Na (NaV) channels where seal resistance and access resistance are critical for good voltage control. In automated patch clamp, suction is applied from underneath the patch clamp chip to attract a cell to the hole and obtain a good seal. Since the patch clamp aperture cannot be moved to improve the seal like the patch clamp pipette in manual patch clamp, automated patch clamp manufacturers use internal fluoride to improve the success rate for obtaining GΩ seals. However, internal fluoride can affect voltage-dependence of activation and inactivation, as well as affecting internal second messenger systems and therefore, it is desirable to have the option to perform experiments using physiological, fluoride-free internal solution. We have developed an approach for high throughput fluoride-free recordings on a 384-well based automated patch clamp system with success rates >40% for GΩ seals. We demonstrate this method using hERG expressed in HEK cells, as well as NaV1.5, NaV1.7, and KCa3.1 expressed in CHO cells. We describe the advantages and disadvantages of using fluoride and provide examples of where fluoride can be used, where caution should be exerted and where fluoride-free solutions provide an advantage over fluoride-containing solutions. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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46. Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7.
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Gaoxingyu Huang, Qiurong Wu, Zhangqiang Li, Xueqin Jin, Xiaoshuang Huang, Tong Wu, Xiaojing Pan, and Nieng Yan
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VOLTAGE-gated ion channels , *DRUG discovery , *ROTATIONAL motion , *ANALGESICS - Abstract
Voltage-gated sodium (Nav) channel Nav1.7 has been targeted for the development of nonaddictive pain killers. Structures of Nav1.7 in distinct functional states will offer an advanced mechanistic understanding and aid drug discovery. Here we report the cryoelectron microscopy analysis of a human Nav1.7 variant that, with 11 rationally introduced point mutations, has a markedly right-shifted activation voltage curve with V1/2 reaching 69 mV. The voltage-sensing domain in the first repeat (VSDI) in a 2.7-Å resolution structure displays a completely down (deactivated) conformation. Compared to the structure of WT Nav1.7, three gating charge (GC) residues in VSDI are transferred to the cytosolic side through a combination of helix unwinding and spiral sliding of S4I and ~20° domain rotation. A conserved WNΦΦD motif on the cytoplasmic end of S3I stabilizes the down conformation of VSDI. One GC residue is transferred in VSDII mainly through helix sliding. Accompanying GC transfer in VSDI and VSDII, rearrangement and contraction of the intracellular gate is achieved through concerted movements of adjacent segments, including S4-5I, S4-5II, S5II, and all S6 segments. Our studies provide important insight into the electromechanical coupling mechanism of the single-chain voltage-gated ion channels and afford molecular interpretations for a number of pain-associated mutations whose pathogenic mechanism cannot be revealed from previously reported Nav structures. [ABSTRACT FROM AUTHOR] more...
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- 2022
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47. Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of NaV1.7.
- Author
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Sun, Shaoyi, Chowdhury, Sultan, Hemeon, Ivan, Hasan, Abid, Wilson, Michael S., Bergeron, Phillipe, Jia, Qi, Zenova, Alla Y., Grimwood, Mike E., Gong, Wei, Decker, Shannon M., Bichler, Paul, Andrez, Jean-Christophe, Focken, Thilo, Ngyuen, Theresa, Zhu, Jiuxiang, White, Andrew D., Bankar, Girish, Howard, Sarah, and Chang, Elaine more...
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SODIUM channels , *ASYMMETRIC synthesis , *CYCLOPENTANE , *TRANSGENIC mice , *ADAMANTANE , *CARBOXYLIC acids - Abstract
[Display omitted] • Proline analogs showed good potency on Na V 1.7 and selectivity against Na V 1.5 but possessed poor PK. • Cyclopentane carboxylic acid 31 provided an excellent balance between Na V 1.7 potency, selectivity over Na V 1.5, and PK properties. • An asymmetric synthesis of compound 31 was described. Discovery efforts leading to the identification of cyclopentane carboxylic acid 31 , a potent inhibitor of Na V 1.7 that showed high selectivity over Na V 1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of 31 include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na V 1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK. [ABSTRACT FROM AUTHOR] more...
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- 2025
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48. Cell specific regulation of NaV1.7 activity and trafficking in rat nodose ganglia neurons
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Santiago I. Loya-López, Paz Duran, Dongzhi Ran, Aida Calderon-Rivera, Kimberly Gomez, Aubin Moutal, and Rajesh Khanna
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NaV1.7 ,Trafficking ,CRMP2 ,Numb ,Nodose ganglia neurons ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The voltage-gated sodium NaV1.7 channel sets the threshold for electrogenesis. Mutations in the gene encoding human NaV1.7 (SCN9A) cause painful neuropathies or pain insensitivity. In dorsal root ganglion (DRG) neurons, activity and trafficking of NaV1.7 are regulated by the auxiliary collapsin response mediator protein 2 (CRMP2). Specifically, preventing addition of a small ubiquitin-like modifier (SUMO), by the E2 SUMO-conjugating enzyme Ubc9, at lysine-374 (K374) of CRMP2 reduces NaV1.7 channel trafficking and activity. We previously identified a small molecule, designated 194, that prevented CRMP2 SUMOylation by Ubc9 to reduce NaV1.7 surface expression and currents, leading to a reduction in spinal nociceptive transmission, and culminating in normalization of mechanical allodynia in models of neuropathic pain. In this study, we investigated whether NaV1.7 control via CRMP2-SUMOylation is conserved in nodose ganglion (NG) neurons. This study was motivated by our desire to develop 194 as a safe, non-opioid substitute for persistent pain, which led us to wonder how 194 would impact NaV1.7 in NG neurons, which are responsible for driving the cough reflex. We found functioning NaV1.7 channels in NG neurons; however, they were resistant to downregulation via either CRMP2 knockdown or pharmacological inhibition of CRMP2 SUMOylation by 194. CRMP2 SUMOylation and interaction with NaV1.7 was consered in NG neurons but the endocytic machinery was deficient in the endocytic adaptor protein Numb. Overexpression of Numb rescued CRMP2-dependent regulation on NaV1.7, rendering NG neurons sensitive to 194. Altogether, these data point at the existence of cell-specific mechanisms regulating NaV1.7 trafficking. more...
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- 2022
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49. Fifteen years of NaV1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy?
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Eagles, David A., Chow, Chun Yuen, and King, Glenn F.
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CONOTOXINS , *PHARMACOLOGY , *MEMBRANE proteins , *ANIMAL models in research , *CLINICAL trials - Abstract
In 2006, humans with a congenital insensitivity to pain (CIP) were found to lack functional NaV1.7 channels. In the subsequent 15 years there was a rush to develop selective inhibitors of NaV1.7 channels with the goal of producing broadly effective analgesics without the problems of addiction and tolerance associated with opioids. Pharmacologically, this mission has been highly successful, leading to a number of highly potent and selective inhibitors of NaV1.7 channels. However, there are very few examples where these inhibitors have yielded effective analgesia in preclinical pain models or human clinical trials. In this review, we summarise the role of the NaV1.7 channel in nociception, its history as a therapeutic target and the quest to develop potent inhibitors of this channel. Finally, we discuss possible reasons why the pain‐free state seen in humans with CIP has been so difficult to replicate pharmacologically. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc [ABSTRACT FROM AUTHOR] more...
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- 2022
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50. Examination of the contribution of Nav1.7 to axonal propagation in nociceptors.
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Goodwin, George, McMurray, Sheridan, Stevens, Edward B., Denk, Franziska, and McMahon, Stephen B.
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NEURAL physiology , *PAIN , *SODIUM channel blockers , *SENSORY receptors , *ANIMAL experimentation , *SENSORY ganglia , *NOCICEPTORS , *ACTION potentials , *MEMBRANE transport proteins , *ANIMALS , *MICE , *PHARMACODYNAMICS - Abstract
Abstract: Nav1.7 is a promising drug target for the treatment of pain. However, there is a mismatch between the analgesia produced by Nav1.7 loss-of-function and the peripherally restricted Nav1.7 inhibitors, which may reflect a lack of understanding of the function of Nav1.7 in the transmission of nociceptive information. In the periphery, the role of Nav1.7 in transduction at nociceptive peripheral terminals has been comprehensively examined, but its role in axonal propagation in these neurons is less clearly defined. In this study, we examined the contribution of Nav1.7 to axonal propagation in nociceptors using sodium channel blockers in in vivo electrophysiological and calcium imaging recordings in mice. Using the sodium channel blocker tetrodotoxin (TTX) (1-10 µM) to inhibit Nav1.7 and other tetrodotoxin-sensitive sodium channels along the sciatic nerve, we first showed that around two-thirds of nociceptive L4 dorsal root ganglion neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. By contrast, nearly all large-sized cutaneous afferents (95%-100%) were blocked by axonal TTX. Many cutaneous nociceptors resistant to TTX were polymodal (57%) and capsaicin sensitive (57%). Next, we applied PF-05198007 (300 nM-1 µM) to the sciatic nerve between stimulating and recording sites to selectively block axonal Nav1.7 channels. One hundred to three hundred nanomolar PF-05198007 blocked propagation in 63% of C-fiber sensory neurons, whereas similar concentrations produced minimal block (5%) in rapidly conducting A-fiber neurons. We conclude that Nav1.7 is essential for axonal propagation in around two-thirds of nociceptive cutaneous C-fiber neurons and a lower proportion (≤45%) of nociceptive neurons innervating muscle. [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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