Ca2+-sensing receptor regulates neuronal excitability via Kv7 channel and Gi/oprotein signalling

Abstract

AbstractNeuropathic pain, a debilitating condition with unmet medical needs, can be charactarised as hyperexcitability of nociceptive neurons caused by dysfunction of ion channels. Voltage-gated potassium channel type 7 (Kv7), responsible for maintaining neuronal resting membrane potential and thus neuronal exitability, resides under tight control of G protein-coupled receptors (GPCR). Calcium-sensing receptor (CaSR) is a GPCR that is known to regulate activity of numerous ion channels, but whether CaSR could control Kv7 channel function has been unexplored until now. Our results demonstrate that CaSR is expressed in recombinant cell models, human induced pluripotent stem cell (hiPSC)-derived nociceptive-like neurons and mouse dorsal root ganglia 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/oprotein/adenylate cyclase/cyclic adenosine monophosphate/protein kinase A signalling cascade. Suppression of CaSR function rescued hiPSC-derived nociceptive-like neurons from algogenic cocktail-induced hyperexcitability. To conclude, this study demonstrates that CaSR-Kv7.2/7.3 channel crosslink via the Gi/oprotein signalling pathway effectively regulates neuronal excitability, providing a feasible pharmacological target for neuronal hyperexcitability management in neuropathic pain.