10 results on '"Isensee, J."'
Search Results
2. Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling
- Author
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Overhoff, M., primary, Tellkamp, F., additional, Hess, S., additional, Tutas, J., additional, Tolve, M., additional, Faerfers, M., additional, Ickert, L., additional, Mohammadi, M., additional, De Bruyckere, E., additional, Kallergi, E., additional, Dell Vedove, A., additional, Nikoletopoulou, V., additional, Wirth, B., additional, Isensee, J., additional, Hucho, T., additional, Puchkov, D., additional, Isbrandt, D., additional, Krüger, M., additional, Kloppenburg, P., additional, and Kononenko, N.L., additional
- Published
- 2022
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3. Diversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling.
- Author
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Pinheiro-Junior EL, Alirahimi E, Peigneur S, Isensee J, Schiffmann S, Erkoc P, Fürst R, Vilcinskas A, Sennoner T, Koludarov I, Hempel BF, Tytgat J, Hucho T, and von Reumont BM
- Subjects
- Animals, MAP Kinase Signaling System drug effects, Phylogeny, Mice, Cyclic AMP-Dependent Protein Kinases metabolism, Cyclic AMP-Dependent Protein Kinases genetics, Evolution, Molecular, Humans, Arthropod Venoms chemistry, Potassium Channels metabolism, Potassium Channels genetics
- Abstract
Background: The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold., Results: Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib
1 and xib13 with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib1 and xib13 increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib13 either originates from the common ancestor of pancrustaceans or earlier while xib1 is more restricted to remipedes. The ten-cysteine scaffolded xib2 emerged from xib1 , a result that is supported by our phylogenetic and machine learning-based analyses., Conclusions: Our functional characterization of synthesized variants of xib1 , xib2 , and xib13 elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib2 with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib1 and xib13 activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib1 , xib2, and xib13 requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib2 from xib1 . Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms., (© 2024. The Author(s).)- Published
- 2024
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4. Emergence of nociceptive functionality and opioid signaling in human induced pluripotent stem cell-derived sensory neurons.
- Author
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Röderer P, Belu A, Heidrich L, Siobal M, Isensee J, Prolingheuer J, Janocha E, Valdor M, Hagendorf S, Bahrenberg G, Opitz T, Segschneider M, Haupt S, Nitzsche A, Brüstle O, and Hucho T
- Subjects
- Humans, Analgesics, Opioid, Colforsin pharmacology, Nociception, Sensory Receptor Cells, Ion Channels, Induced Pluripotent Stem Cells
- Abstract
Abstract: Induced pluripotent stem cells (iPSCs) have enabled the generation of various difficult-to-access cell types such as human nociceptors. A key challenge associated with human iPSC-derived nociceptors (hiPSCdNs) is their prolonged functional maturation. While numerous studies have addressed the expression of classic neuronal markers and ion channels in hiPSCdNs, the temporal development of key signaling cascades regulating nociceptor activity has remained largely unexplored. In this study, we used an immunocytochemical high-content imaging approach alongside electrophysiological staging to assess metabotropic and ionotropic signaling of large scale-generated hiPSCdNs across 70 days of in vitro differentiation. During this period, the resting membrane potential became more hyperpolarized, while rheobase, action potential peak amplitude, and membrane capacitance increased. After 70 days, hiPSCdNs exhibited robust physiological responses induced by GABA, pH shift, ATP, and capsaicin. Direct activation of protein kinase A type II (PKA-II) through adenylyl cyclase stimulation with forskolin resulted in PKA-II activation at all time points. Depolarization-induced activation of PKA-II emerged after 35 days of differentiation. However, effective inhibition of forskolin-induced PKA-II activation by opioid receptor agonists required 70 days of in vitro differentiation. Our results identify a pronounced time difference between early expression of functionally important ion channels and emergence of regulatory metabotropic sensitizing and desensitizing signaling only at advanced stages of in vitro cultivation, suggesting an independent regulation of ionotropic and metabotropic signaling. These data are relevant for devising future studies into the development and regulation of human nociceptor function and for defining time windows suitable for hiPSCdN-based drug discovery., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)
- Published
- 2023
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5. Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake.
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Klein I, Isensee J, Wiesen MHJ, Imhof T, Wassermann MK, Müller C, Hucho T, Koch M, and Lehmann HC
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- Humans, Paclitaxel adverse effects, Glycyrrhizic Acid pharmacology, Neurons metabolism, Membrane Transport Proteins, Organic Anion Transporters metabolism, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases prevention & control
- Abstract
Peripheral neuropathy is a common side effect of cancer treatment with paclitaxel. The mechanisms by which paclitaxel is transported into neurons, which are essential for preventing neuropathy, are not well understood. We studied the uptake mechanisms of paclitaxel into neurons using inhibitors for endocytosis, autophagy, organic anion-transporting polypeptide (OATP) drug transporters, and derivatives of paclitaxel. RT-qPCR was used to investigate the expression levels of OATPs in different neuronal tissues and cell lines. OATP transporters were pharmacologically inhibited or modulated by overexpression and CRISPR/Cas9-knock-out to investigate paclitaxel transport in neurons. Through these experiments, we identified OATP1A1 and OATP1B2 as the primary neuronal transporters for paclitaxel. In vitro inhibition of OATP1A1 and OAT1B2 by glycyrrhizic acid attenuated neurotoxicity, while paclitaxel's antineoplastic effects were sustained in cancer cell lines. In vivo, glycyrrhizic acid prevented paclitaxel-induced toxicity and improved behavioral and electrophysiological measures. This study indicates that a set of OATPs are involved in paclitaxel transport into neurons. The inhibition of OATP1A1 and OATP1B2 holds a promising strategy to prevent paclitaxel-induced peripheral neuropathy.
- Published
- 2023
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6. Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse.
- Author
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Overhoff M, Tellkamp F, Hess S, Tolve M, Tutas J, Faerfers M, Ickert L, Mohammadi M, De Bruyckere E, Kallergi E, Delle Vedove A, Nikoletopoulou V, Wirth B, Isensee J, Hucho T, Puchkov D, Isbrandt D, Krueger M, Kloppenburg P, and Kononenko NL
- Subjects
- Mice, Animals, Cyclic AMP-Dependent Protein Kinases metabolism, Signal Transduction, Autophagy, Synapses metabolism, Neurons metabolism
- Abstract
Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, by combining mouse models of neuron-specific ATG5 deficiency in either excitatory or inhibitory neurons with quantitative proteomics, high-content microscopy, and live-imaging approaches, we show that autophagy protein ATG5 functions in neurons to regulate cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA-R1, which sequesters the PKA catalytic subunit and diminishes cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins that mediate AMPAR trafficking. Furthermore, ATG5 deletion in glutamatergic neurons augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction., (© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2022
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7. Stress anisotropy in confined populations of growing rods.
- Author
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Isensee J, Hupe L, Golestanian R, and Bittihn P
- Subjects
- Anisotropy
- Abstract
A central feature of living matter is its ability to grow and multiply. The mechanical activity associated with growth produces both macroscopic flows shaped by confinement, and striking self-organization phenomena, such as orientational order and alignment, which are particularly prominent in populations of rod-shaped bacteria due to their nematic properties. However, how active stresses, passive mechanical interactions and flow-induced effects interact to give rise to the observed global alignment patterns remains elusive. Here, we study in silico colonies of growing rod-shaped particles of different aspect ratios confined in channel-like geometries. A spatially resolved analysis of the stress tensor reveals a strong relationship between near-perfect alignment and an inversion of stress anisotropy for particles with large length-to-width ratios. We show that, in quantitative agreement with an asymptotic theory, strong alignment can lead to a decoupling of active and passive stresses parallel and perpendicular to the direction of growth, respectively. We demonstrate the robustness of these effects in a geometry that provides less restrictive confinement and introduces natural perturbations in alignment. Our results illustrate the complexity arising from the inherent coupling between nematic order and active stresses in growing active matter, which is modulated by geometric and configurational constraints due to confinement.
- Published
- 2022
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8. A DNA origami rotary ratchet motor.
- Author
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Pumm AK, Engelen W, Kopperger E, Isensee J, Vogt M, Kozina V, Kube M, Honemann MN, Bertosin E, Langecker M, Golestanian R, Simmel FC, and Dietz H
- Subjects
- Hydrogen-Ion Concentration, Motion, Movement, Osmolar Concentration, Proton-Translocating ATPases chemistry, Proton-Translocating ATPases metabolism, Stochastic Processes, Temperature, Thermodynamics, DNA chemistry, Facilitated Diffusion, Molecular Motor Proteins chemistry, Molecular Motor Proteins metabolism
- Abstract
To impart directionality to the motions of a molecular mechanism, one must overcome the random thermal forces that are ubiquitous on such small scales and in liquid solution at ambient temperature. In equilibrium without energy supply, directional motion cannot be sustained without violating the laws of thermodynamics. Under conditions away from thermodynamic equilibrium, directional motion may be achieved within the framework of Brownian ratchets, which are diffusive mechanisms that have broken inversion symmetry
1-5 . Ratcheting is thought to underpin the function of many natural biological motors, such as the F1 F0 -ATPase6-8 , and it has been demonstrated experimentally in synthetic microscale systems (for example, to our knowledge, first in ref.3 ) and also in artificial molecular motors created by organic chemical synthesis9-12 . DNA nanotechnology13 has yielded a variety of nanoscale mechanisms, including pivots, hinges, crank sliders and rotary systems14-17 , which can adopt different configurations, for example, triggered by strand-displacement reactions18,19 or by changing environmental parameters such as pH, ionic strength, temperature, external fields and by coupling their motions to those of natural motor proteins20-26 . This previous work and considering low-Reynolds-number dynamics and inherent stochasticity27,28 led us to develop a nanoscale rotary motor built from DNA origami that is driven by ratcheting and whose mechanical capabilities approach those of biological motors such as F1 F0 -ATPase., (© 2022. The Author(s).)- Published
- 2022
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9. Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer.
- Author
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Ratz L, Brambillasca C, Bartke L, Huetzen MA, Goergens J, Leidecker O, Jachimowicz RD, van de Ven M, Proost N, Siteur B, de Korte-Grimmerink R, Bouwman P, Pulver EM, de Bruijn R, Isensee J, Hucho T, Pandey G, van Lohuizen M, Mallmann P, Reinhardt HC, Jonkers J, and Puppe J
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mice, Synthetic Lethal Mutations, Antineoplastic Combined Chemotherapy Protocols pharmacology, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins metabolism, BRCA1 Protein deficiency, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Indoles pharmacology, Protein Kinase Inhibitors pharmacology, Pyridones pharmacology
- Abstract
Background: The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype., Methods: Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy. To validate the role of EZH2 as a therapeutic target and to identify new synergistic drug combinations, we performed a high-throughput drug combination screen in various cell lines derived from BRCA1-deficient and -proficient mouse mammary tumors., Results: We identified the combined inhibition of EZH2 and the proximal DNA damage response kinase ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-deficient breast tumors. We show that the combined treatment with the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress, and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors., Conclusion: Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1-mutant breast cancer., (© 2022. The Author(s).)
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- 2022
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10. Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2 + DRG sensory neurons.
- Author
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Yang NJ, Isensee J, Neel DV, Quadros AU, Zhang HB, Lauzadis J, Liu SM, Shiers S, Belu A, Palan S, Marlin S, Maignel J, Kennedy-Curran A, Tong VS, Moayeri M, Röderer P, Nitzsche A, Lu M, Pentelute BL, Brüstle O, Tripathi V, Foster KA, Price TJ, Collier RJ, Leppla SH, Puopolo M, Bean BP, Cunha TM, Hucho T, and Chiu IM
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- Animals, Ganglia, Spinal metabolism, Humans, Mice, Nociceptors metabolism, Pain, Receptors, Peptide metabolism, Anthrax microbiology, Anthrax therapy, Bacillus anthracis metabolism, Bacterial Toxins metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Na
v 1.8+ or Advillin+ neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2022
- Full Text
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