Trigeminal neuralgia

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: May 30, 2024

Language: Английский

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Intranasal CRMP2-Ubc9 inhibitor regulates NaV1.7 to alleviate trigeminal neuropathic pain

Pain, Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 26, 2023

Abstract Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that results part from increased SUMOylation collapsin response mediator protein 2 (CRMP2), leading an CRMP2/Na interaction and functional activity 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 mediated by the SUMO-conjugating enzyme Ubc9. further demonstrated effectively reduces dorsal root ganglia alleviated inflammatory Here, used a comprehensive array approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, behavioral analyses, assess implications regulation (TG) neurons. confirmed expression Scn9a Dpysl2 UBE2I within TG Furthermore, found between 1.7, with being SUMOylated these ganglia. Disrupting uncoupled interaction, impeded diffusion on plasma membrane, subsequently diminished activity. Compound also led reduction neuron excitability. Finally, when intranasally administered rats constriction injury infraorbital nerve, significantly decreased nociceptive behaviors. Collectively, our findings underscore critical role regulating neurons, emphasizing importance indirect modulation

Language: Английский

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The T-type calcium channelosome

Pflügers Archiv - European Journal of Physiology, Journal Year: 2023, Volume and Issue: 476(2), P. 163 - 177

Published: Dec. 1, 2023

Language: Английский

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Electrophysiological characterization of a Cav3.2 calcium channel missense variant associated with epilepsy and hearing loss

Molecular Brain, Journal Year: 2023, Volume and Issue: 16(1)

Published: Sept. 21, 2023

Abstract T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different channels. Recently, new heterozygous missense mutation CACNA1H gene that encodes Ca v 3.2 channel was reported patient presenting with epilepsy and hearing loss—apparently first to be associated sensorineural condition. This leads substitution an arginine at position 132 histidine (R132H) proximal extracellular end second transmembrane helix 3.2. In this study, we report electrophysiological characterization variant using whole-cell patch clamp recordings tsA-201 cells. Our data reveal minor gating alterations evidenced mild increase current density slower recovery from inactivation, as well enhanced sensitivity external pH change. To what extend these biophysical changes induced R132H contribute observed pathogenicity remains open question will necessitate analysis additional variants same pathologies.

Language: Английский

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Review possible therapies to address clinical manifestations including symptoms and signs and abnormal results of metabolic, biochemical, gene-based studies

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 81 - 117

Published: Nov. 1, 2024

Language: Английский

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Intranasal CRMP2-Ubc9 Inhibitor Regulates Na_V1.7 to Alleviate Trigeminal Neuropathic Pain

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 17, 2023

Abstract Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that results part from increased SUMOylation collapsin response mediator protein 2 (CRMP2), leading an CRMP2/Na interaction and functional activity 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 mediated by the SUMO-conjugating enzyme Ubc9. further demonstrated effectively reduces dorsal root ganglia alleviated inflammatory Here, employed a comprehensive array investigative approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, behavioral analyses, assess implications regulation (TG) neurons. confirmed expression Scn9a Dpysl2 UBE2I within TG Furthermore, found between 1.7, with being SUMOylated these ganglia. Disrupting uncoupled interaction, impeded diffusion on plasma membrane, subsequently diminished activity. Compound also led reduction neuron excitability. Finally, when intranasally administered rats constriction injury infraorbital nerve (CCI-ION), significantly decreased nociceptive behaviors. Collectively, our findings underscore critical role regulating neurons, emphasizing importance indirect modulation

Language: Английский

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UnCRMPing Nav1.7 to treat trigeminal neuropathic pain

Pain, Journal Year: 2023, Volume and Issue: 165(3), P. 493 - 495

Published: Sept. 6, 2023

aDepartment of Clinical Neurosciences, Cumming School Medicine, Alberta Children's Hospital Research Institute, University Calgary, AB, Canada bCumming Hotchkiss Brain Sponsorships or competing interests that may be relevant to content are disclosed at the end this article.

Language: Английский

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