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

Chuinsiri, Nontawat, Siraboriphantakul, Nannapat, Kendall, Luke, Yarova, Polina, Nile, Christopher J., Song, Bing ORCID: https://orcid.org/0000-0001-9356-2333, Obara, Ilona, Durham, Justin and Telezhkin, Vsevolod 2024. Calcium‐sensing receptor regulates Kv7 channels via Gi/o protein signalling and modulates excitability of human induced pluripotent stem cell‐derived nociceptive‐like neurons. British Journal of Pharmacology 181 (15) , pp. 2676-2696. 10.1111/bph.16349

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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 Gi/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 Gi/o protein signalling pathway, effectively regulates neuronal excitability, providing a feasible pharmacological target for neuronal hyperexcitability management in neuropathic pain.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	0007-1188
Date of First Compliant Deposit:	18 April 2024
Date of Acceptance:	15 February 2024
Last Modified:	20 Aug 2024 13:48
URI:	https://orca.cardiff.ac.uk/id/eprint/168135

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