RT Journal Article SR Electronic T1 CaSR modulates sodium channel-mediated Ca2+-dependent excitability JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.03.03.433701 DO 10.1101/2021.03.03.433701 A1 Briana J. Martiszus A1 Timur Tsintsadze A1 Wenhan Chang A1 Stephen M. Smith YR 2021 UL http://biorxiv.org/content/early/2021/03/04/2021.03.03.433701.1.abstract AB Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge reducing voltage-dependent sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that action potential (AP) firing rates increased in wild-type (WT), but not CaSR null mutant (Casr-/-) neocortical neurons, following the switch from physiological to reduced Ca2+-containing Tyrode. However, after membrane potential correction, AP firing increased similarly in both genotypes inconsistent with CaSR regulation of NALCN. Activation of VGSCs was the dominant contributor to the increase in excitability after the [Ca2+]o change. VGSC conductance-voltage relationships were hyperpolarized by decreasing [Ca2+]o for Casr-/- neurons indicating CaSR contributes to [Ca2+]o-dependent excitability via VGSCs. Regulation of VGSC gating by [Ca2+]o is the key mechanism mediating [Ca2+]o-dependent changes in neocortical neuron excitability and CaSR influences neuronal excitability by its effects on VGSC gating.Competing Interest StatementThe authors have declared no competing interest.