12 results on '"Denton, Jerod S."'
Search Results
2. Kir4.2 mediates proximal potassium effects on glutaminase activity and kidney injury.
- Author
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Terker, Andrew S., Zhang, Yahua, Arroyo, Juan Pablo, Cao, Shirong, Wang, Suwan, Fan, Xiaofeng, Denton, Jerod S., Zhang, Ming-Zhi, and Harris, Raymond C.
- Abstract
Inadequate potassium (K
+ ) consumption correlates with increased mortality and poor cardiovascular outcomes. Potassium effects on blood pressure have been described previously; however, whether or not low K+ independently affects kidney disease progression remains unclear. Here, we demonstrate that dietary K+ deficiency causes direct kidney injury. Effects depend on reduced blood K+ and are kidney specific. In response to reduced K+ , the channel Kir4.2 mediates altered proximal tubule (PT) basolateral K+ flux, causing intracellular acidosis and activation of the enzyme glutaminase and the ammoniagenesis pathway. Deletion of either Kir4.2 or glutaminase protects from low-K+ injury. Reduced K+ also mediates injury and fibrosis in a model of aldosteronism. These results demonstrate that the PT epithelium, like the distal nephron, is K+ sensitive, with reduced blood K+ causing direct PT injury. Kir4.2 and glutaminase are essential mediators of this injury process, and we identify their potential for future targeting in the treatment of chronic kidney disease. [Display omitted] • K+ deficiency causes kidney-specific injury and inflammation • Injury effects are dependent on the proximal K+ channel Kir4.2 • Kir4.2 mediates activation of the ammoniagenesis pathway under low-K+ conditions • Kidney deletion of glutaminase prevents low-K+ -mediated kidney injury Terker et al. demonstrate that dietary K+ deficiency causes kidney-specific injury and inflammation. Effects are mediated by the proximal tubule basolateral K+ channel Kir4.2, which promotes ammoniagenesis in response to reduced blood K+ levels. Deletion of this channel or the enzyme glutaminase protect animals from low-K+ -mediated kidney injury. [ABSTRACT FROM AUTHOR]- Published
- 2022
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3. Lactate activation of α-cell KATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca2+ entry.
- Author
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Zaborska, Karolina E., Dadi, Prasanna K., Dickerson, Matthew T., Nakhe, Arya Y., Thorson, Ariel S., Schaub, Charles M., Graff, Sarah M., Stanley, Jade E., Kondapavuluru, Roy S., Denton, Jerod S., and Jacobson, David A.
- Abstract
Elevations in pancreatic α-cell intracellular Ca
2+ ([Ca2+ ] i) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-cell Ca2+ handling is unknown. Lactate enters cells through monocarboxylate transporters (MCTs) and is also produced during glycolysis by lactate dehydrogenase A (LDHA), an enzyme expressed in α-cells. As lactate activates ATP-sensitive K+ (K ATP) channels in cardiomyocytes, lactate may also modulate α-cell K ATP. Therefore, this study investigated how lactate signaling controls α-cell Ca2+ handling and GCG secretion. Mouse and human islets were used in combination with confocal microscopy, electrophysiology, GCG immunoassays, and fluorescent thallium flux assays to assess α-cell Ca2+ handling, V m , K ATP currents, and GCG secretion. Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) α-cell [Ca2+ ] i fluctuations only under low-glucose conditions (1 mM) but had no effect on β- or δ-cells [Ca2+ ] i. Glyburide inhibition of K ATP channels restored α-cell [Ca2+ ] i fluctuations in the presence of lactate. Lactate transport into α-cells via MCTs hyperpolarized mouse (14 ± 1 mV) and human (12 ± 1 mV) α-cell V m and activated K ATP channels. Interestingly, pyruvate showed a similar K ATP activation profile and α-cell [Ca2+ ] i inhibition as lactate. Lactate-induced inhibition of α-cell [Ca2+ ] i influx resulted in reduced GCG secretion in mouse (62 ± 6%) and human (43 ± 13%) islets. These data demonstrate for the first time that lactate entry into α-cells through MCTs results in K ATP activation, V m hyperpolarization, reduced [Ca2+ ] i , and inhibition of GCG secretion. Thus, taken together, these data indicate that lactate either within α-cells and/or elevated in serum could serve as important modulators of α-cell function. Image 1 • Lactate reduces islet α-cell Ca2+ entry under low glucose conditions. • Lactate does not alter β- or δ-cell Ca2+ handling under low glucose conditions. • Lactate enters islet α-cells through monocarboxylate transporters. • Lactate hyperpolarizes islet α-cell membrane potential by activating K ATP channels. • Lactate reduces mouse and human islet glucagon secretion. [ABSTRACT FROM AUTHOR]- Published
- 2020
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4. Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics.
- Author
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Swale, Daniel R, Kharade, Sujay V, and Denton, Jerod S
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POTASSIUM channels , *PHARMACOLOGY , *TARGETED drug delivery , *HEART physiology , *KIDNEY physiology , *BIOCHEMICAL mechanism of action - Abstract
Highlights: [•] Some Kir channels are putative drug targets, but their pharmacology is limited. [•] Newly discovered inhibitors or activators of Kir2.x, 4.1, and 7.1 are discussed. [•] Mechanisms of action involve pore-lining residues that control rectification. [•] This work is a critical first step toward developing more specific modulators. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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5. Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) dual activator tool compound: Multi-dimensional optimization of BL-1249.
- Author
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Iwaki, Yuzo, Yashiro, Kentaro, Kokubo, Masaya, Mori, Takahiro, Wieting, Joshua M., McGowan, Kevin M., Bridges, Thomas M., Engers, Darren W., Denton, Jerod S., Kurata, Haruto, and Lindsley, Craig W.
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POTASSIUM channels , *ROBUST optimization , *STRUCTURE-activity relationships , *ION channels , *POTASSIUM ions - Abstract
• First detailed SAR account around TREK1/2 activators. • First optimization campaign directed at BL-1249. • Discovery of new in vitro and in vivo tool compound, ONO-2960632/VU6011992. This letter describes a focused, multi-dimensional optimization campaign around BL-1249, a fenamate class non-steroidal anti-inflammatory and a known activator of the K 2P potassium channels TREK-1 (K 2P 2.1) and TREK-2 (K 2P 10.1). While BL-1249 has been widely profiled in vitro as a dual TREK-1/2 activator, poor physicochemical and DMPK properties have precluded a deeper understanding of the therapeutic potential of these key K 2P channels across a broad spectrum of peripheral and central human disease. Here, we report multi-dimensional SAR that led to a novel TREK-1/2 dual activator chemotype, exemplified by ONO-2960632/VU6011992, with improved DMPK properties, representing a new lead for further optimization towards robust in vivo tool compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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6. G protein-coupled receptors differentially regulate glycosylation and activity of the inwardly rectifying potassium channel Kir7.1.
- Author
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Carrington, Sheridan J., Hernandez, Ciria C., Swale, Daniel R., Aluko, Oluwatosin A., Denton, Jerod S., and Cone, Roger D.
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G protein coupled receptors , *GLYCOSYLATION , *POTASSIUM channels , *WESTERN immunoblotting , *MELANOCORTIN receptors - Abstract
Kir7.1 is an inwardly rectifying potassium channel with important roles in the regulation of the membrane potential in retinal pigment epithelium, uterine smooth muscle, and hypothalamic neurons. Regulation of G protein-coupled inwardly rectifying potassium (GIRK) channels by G protein-coupled receptors (GPCRs) via the G protein βγ subunits has been well characterized. However, how Kir channels are regulated is incompletely understood. We report here that Kir7.1 is also regulated by GPCRs, but through a different mechanism. Using Western blotting analysis, we observed that multiple GPCRs tested caused a striking reduction in the complex glycosylation of Kir7.1. Further, GPCR-mediated reduction of Kir7.1 glycosylation in HEK293T cells did not alter its expression at the cell surface but decreased channel activity. Of note, mutagenesis of the sole Kir7.1 glycosylation site reduced conductance and open probability, as indicated by single-channel recording. Additionally, we report that the L241P mutation of Kir7.1 associated with Lebers congenital amaurosis (LCA), an inherited retinal degenerative disease, has significantly reduced complex glycosylation. Collectively, these results suggest that Kir7.1 channel glycosylation is essential for function, and this activity within cells is suppressed by most GPCRs. The melanocortin-4 receptor (MC4R), a GPCR previously reported to induce ligand-regulated activity of this channel, is the only GPCR tested that does not have this effect on Kir7.1. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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7. Inward rectifier potassium (Kir) channels in the soybean aphid Aphis glycines: Functional characterization, pharmacology, and toxicology.
- Author
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Piermarini, Peter M., Inocente, Edna Alfaro, Acosta, Nuris, Hopkins, Corey R., Denton, Jerod S., and Michel, Andrew P.
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SOYBEAN diseases & pests , *APHIDS , *INSECT genomes , *APHIS glycines , *POTASSIUM channels , *PHARMACOLOGY , *TOXICOLOGY - Abstract
Graphical abstract Highlights • The genome of Aphis glycines possessed 2 Kir channel genes: ApKir1 and ApKir2. • ApKir1 and ApKir2 formed barium-inhibitable Kir channels in Xenopus oocytes. • ApKir1 produced larger K+-currents with stronger rectification compared to ApKir2. • ApKir1 was more sensitive to barium compared to ApKir2. • Small molecule inhibition of Kir channels in vivo was lethal to aphids within 24 h. Abstract Inward rectifier K+ (Kir) channels contribute to a variety of physiological processes in insects and are emerging targets for insecticide development. Previous studies on insect Kir channels have primarily focused on dipteran species (e.g., mosquitoes, fruit flies). Here we identify and functionally characterize Kir channel subunits in a hemipteran insect, the soybean aphid Aphis glycines , which is an economically important insect pest and vector of soybeans. From the transcriptome and genome of Ap. glycines we identified two cDNAs, ApKir1 and ApKir2, encoding Kir subunits that were orthologs of insect Kir1 and Kir2, respectively. Notably, a gene encoding a Kir3 subunit was absent from the transcriptome and genome of Ap. glycines , similar to the pea aphid Acyrthosiphon pisum. Heterologous expression of ApKir1 and ApKir2 in Xenopus laevis oocytes enhanced K+-currents in the plasma membrane; these currents were inhibited by barium and the small molecule VU041. Compared to ApKir2, ApKir1 mediated currents that were larger in magnitude, more sensitive to barium, and less inhibited by small molecule VU041. Moreover, ApKir1 exhibited stronger inward rectification compared to ApKir2. Topical application of VU041 in adult aphids resulted in dose-dependent mortality within 24 h that was more efficacious than flonicamid, an established insecticide also known to inhibit Kir channels. We conclude that despite the apparent loss of Kir3 genes in aphid evolution, Kir channels are important to aphid survival and represent a promising target for the development of new insecticides. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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8. Synthesis and SAR of a novel Kir6.2/SUR1 channel opener scaffold identified by HTS.
- Author
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Dodd, Cayden J., Chronister, Keagan S., Rathnayake, Upendra, Parr, Lauren C., Li, Kangjun, Chang, Sichen, Mi, Dehui, Days, Emily L., Bauer, Joshua A., Cho, Hyekyung P., Boutaud, Olivier, Denton, Jerod S., Lindsley, Craig W., and Han, Changho
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POTASSIUM channels , *NEUROPEPTIDES , *STRUCTURE-activity relationships , *ION channels , *SECRETION , *ADENOSINE triphosphate - Abstract
[Display omitted] Kir6.2/SUR1 is an ATP-regulated potassium channel that acts as an intracellular metabolic sensor, controlling insulin and appetite-stimulatory neuropeptides secretion. In this Letter, we present the SAR around a novel Kir6.2/SUR1 channel opener scaffold derived from an HTS screening campaign. New series of compounds with tractable SAR trends and favorable potencies are reported. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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9. Dynamic expression of genes encoding subunits of inward rectifier potassium (Kir) channels in the yellow fever mosquito Aedes aegypti.
- Author
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Yang, Zhongxia, Statler, Bethanie-Michelle, Calkins, Travis L., Alfaro, Edna, Esquivel, Carlos J., Rouhier, Matthew F., Denton, Jerod S., and Piermarini, Peter M.
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YELLOW fever , *AEDES aegypti , *GENES , *MESSENGER RNA , *LARVAE - Abstract
Inward rectifier potassium (Kir) channels play fundamental roles in neuromuscular, epithelial, and endocrine function in mammals. Recent research in insects suggests that Kir channels play critical roles in the development, immune function, and excretory physiology of fruit flies and/or mosquitoes. Moreover, our group has demonstrated that mosquito Kir channels may serve as valuable targets for the development of novel insecticides. Here we characterize the molecular expression of 5 mRNAs encoding Kir channel subunits in the yellow fever mosquito, Aedes aegypti : Kir1 , Kir2A-c , Kir2B , Kir2B’ , and Kir3 . We demonstrate that 1) Kir mRNA expression is dynamic in whole mosquitoes, Malpighian tubules, and the midgut during development from 4th instar larvae to adult females, 2) Kir2B and Kir3 mRNA levels are reduced in 4th instar larvae when reared in water containing an elevated concentration (50 mM) of KCl, but not NaCl, and 3) Kir mRNAs are differentially expressed in the Malpighian tubules, midgut, and ovaries within 24 h after blood feeding. Furthermore, we provide the first characterization of Kir mRNA expression in the anal papillae of 4th instar larval mosquitoes, which indicates that Kir2A-c is the most abundant. Altogether, the data provide the first comprehensive characterization of Kir mRNA expression in Ae. aegypti and offer insights into the putative physiological roles of Kir subunits in this important disease vector. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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10. Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations.
- Author
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Martin, Gregory M., Rex, Emily A., Devaraneni, Prasanna, Denton, Jerod S., Boodhansingh, Kara E., DeLeon, Diva D., Stanley, Charles A., and Shyng, Show-Ling
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POTASSIUM channels , *ADENOSINE triphosphate , *SULFONYLUREAS , *GENETIC mutation , *MEMBRANE potential - Abstract
ATP-sensitive potassium (KATP) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of KATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects. In the present study, we identified 13 novel SUR1 mutations that cause channel trafficking defects, the majority of which are amenable to pharmacological rescue by glibenclamide and carbamazepine. By contrast, none of the mutant channels were rescued by KATP channel openers. Cross-linking experiments showed that KATP channel inhibitors promoted interactions between the N terminus of Kir6.2 and SUR1, whereas channel openers did not, suggesting the inhibitors enhance intersubunit interactions to overcome channel biogenesis and trafficking defects. Functional studies of rescued mutant channels indicate that most mutants rescued to the cell surface exhibited WT-like sensitivity to ATP, MgADP, and diazoxide. In intact cells, recovery of channel function upon trafficking rescue by reversible sulfonylureas or carbamazepine was facilitated by theKATP channel opener diazoxide. Our study expands the list of KATP channel trafficking mutations whose function can be recovered by pharmacological ligands and provides further insight into the structural mechanism by which channel inhibitors correct channel biogenesis and trafficking defects. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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11. Localization and role of inward rectifier K+ channels in Malpighian tubules of the yellow fever mosquito Aedes aegypti.
- Author
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Piermarini, Peter M., Dunemann, Sonja M., Rouhier, Matthew F., Calkins, Travis L., Raphemot, Rene, Denton, Jerod S., Hine, Rebecca M., and Beyenbach, Klaus W.
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YELLOW fever , *AEDES , *EXANTHEMA , *AEDES aegypti , *EPITHELIAL cells - Abstract
Malpighian tubules of adult female yellow fever mosquitoes Aedes aegypti express three inward rectifier K + (Kir) channel subunits: Ae Kir1, Ae Kir2B and Ae Kir3. Here we 1) elucidate the cellular and membrane localization of these three channels in the Malpighian tubules, and 2) characterize the effects of small molecule inhibitors of Ae Kir1 and Ae Kir2B channels (VU compounds) on the transepithelial secretion of fluid and electrolytes and the electrophysiology of isolated Malpighian tubules. Using subunit-specific antibodies, we found that Ae Kir1 and Ae Kir2B localize exclusively to the basolateral membranes of stellate cells and principal cells, respectively; Ae Kir3 localizes within intracellular compartments of both principal and stellate cells. In isolated tubules bathed in a Ringer solution containing 34 mM K + , the peritubular application of VU590 (10 μM), a selective inhibitor of Ae Kir1, inhibited transepithelial fluid secretion 120 min later. The inhibition brings rates of transepithelial KCl and fluid secretion to 54% of the control without a change in transepithelial NaCl secretion. VU590 had no effect on the basolateral membrane voltage (V bl ) of principal cells, but it significantly reduced the cell input conductance (g in ) to values 63% of the control within ∼90 min. In contrast, the peritubular application of VU625 (10 μM), an inhibitor of both Ae Kir1 and Ae Kir2B, started to inhibit transepithelial fluid secretion as early as 60 min later. At 120 min after treatment, VU625 was more efficacious than VU590, inhibiting transepithelial KCl and fluid secretion to ∼35% of the control without a change in transepithelial NaCl secretion. Moreover, VU625 caused the V bl and g in of principal cells to respectively drop to values 62% and 56% of the control values within only ∼30 min. Comparing the effects of VU590 with those of VU625 allowed us to estimate that Ae Kir1 and Ae Kir2B respectively contribute to 46% and 20% of the transepithelial K + secretion when the tubules are bathed in a Ringer solution containing 34 mM K + . Thus, we uncover an important role of Ae Kir1 and stellate cells in transepithelial K + transport under conditions of peritubular K + challenge. The physiological role of Ae Kir3 in intracellular membranes of both stellate and principal cells remains to be determined. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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12. Molecular and functional characterization of Anopheles gambiae inward rectifier potassium (Kir1) channels: A novel role in egg production.
- Author
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Raphemot, Rene, Estévez-Lao, Tania Y., Rouhier, Matthew F., Piermarini, Peter M., Denton, Jerod S., and Hillyer, Julián F.
- Subjects
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MOSQUITO physiology , *ANOPHELES gambiae , *PHYSIOLOGICAL effects of potassium channels , *INSECT eggs , *INSECT genomes , *REVERSE transcriptase polymerase chain reaction , *BLOOD meal as feed , *RNA interference - Abstract
Inward rectifier potassium (Kir) channels play essential roles in regulating diverse physiological processes. Although Kir channels are encoded in mosquito genomes, their functions remain largely unknown. In this study, we identified the members of the Anopheles gambiae Kir gene family and began to investigate their function. Notably, we sequenced the A. gambiae Kir1 (AgKir1) gene and showed that it encodes all the canonical features of a Kir channel: an ion pore that is composed of a pore helix and a selectivity filter, two transmembrane domains that flank the ion pore, and the so-called G-loop. Heterologous expression of AgKir1 in Xenopus oocytes revealed that this gene encodes a functional, barium-sensitive Kir channel. Quantitative RT-PCR experiments then showed that relative AgKir1 mRNA levels are highest in the pupal stage, and that AgKir1 mRNA is enriched in the adult ovaries. Gene silencing of AgKir1 by RNA interference did not affect the survival of female mosquitoes following a blood meal, but decreased their egg output. These data provide evidence for a new role of Kir channels in mosquito fecundity, and further validates them as promising molecular targets for the development of a new class of mosquitocides to be used in vector control. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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