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Calcium-sensing receptor regulates Kv7 channels via G_i/o protein signalling and modulates excitability of human induced pluripotent stem cell-derived nociceptive-like neurons

Lookup NU author(s): Nontawat Chuinsiri, Dr Polina YarovaORCiD, Dr Christopher NileORCiD, Dr Ilona ObaraORCiD, Professor Justin DurhamORCiD, Dr Seva TelezhkinORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Background and purpose: Neuropathic pain, a debilitating condition with unmet medical needs, can be characterised as hyperexcitability of nociceptive neurons caused by dysfunction of ion channels. Voltage-gated potassium channels type 7 (Kv7), responsible for maintaining neuronal resting membrane potential and thus excitability, reside under tight control of G protein-coupled receptors (GPCRs). Calcium-sensing receptor (CaSR) is a GPCR that regulates the activity of numerous ion channels, but whether CaSR can control Kv7 channel function has been unexplored until now. Experimental approach: Experiments were conducted in recombinant cell models, mouse dorsal root ganglia (DRG) neurons and human induced pluripotent stem cell (hiPSC)-derived nociceptive-like neurons using patch-clamp electrophysiology and molecular biology techniques. Key results: Our results demonstrate that CaSR is expressed in recombinant cell models, hiPSC-derived nociceptive-like neurons and mouse DRG neurons, and its activation induced depolarisation via Kv7.2/7.3 channel inhibition. The CaSR-Kv7.2/7.3 channel crosslink was mediated via the G_i/o protein-adenylate cyclase-cyclicAMP-protein kinase A signalling cascade. Suppression of CaSR function demonstrated a potential to rescue hiPSC-derived nociceptive-like neurons from algogenic cocktail-induced hyperexcitability. Conclusion and implications: This study demonstrates that the CaSR-Kv7.2/7.3 channel crosslink, via a G_i/o protein signalling pathway, effectively regulates neuronal excitability, providing a feasible pharmacological target for neuronal hyperexcitability management in neuropathic pain.

Publication metadata

Author(s): Chuinsiri N, Siraboriphantakul N, Kendall L, Yarova P, Nile CJ, Song B, Obara I, Durham J, Telezhkin V

Publication type: Article

Publication status: Published

Journal: British Journal of Pharmacology

Year: 2024

Volume: 181

Issue: 15

Pages: 2676-2696

Print publication date: 02/07/2024

Online publication date: 16/04/2024

Acceptance date: 15/02/2024

Date deposited: 25/11/2024

ISSN (print): 0007-1188

ISSN (electronic): 1476-5381

Publisher: John Wiley & Sons Ltd.

URL: https://doi.org/10.1111/bph.16349

DOI: 10.1111/bph.16349

Data Access Statement: Data needed to evaluate the conclusions in the paper are present in the paper. Data generated for this study are available from the corresponding author upon reasonable request.

PubMed id: 38627101

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