Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels.

ABSTRACT: Voltage-dependent and Ca2+-dependent inactivation (VDI and CDI, respectively) of CaV channels are two biologically consequential feedback mechanisms that fine-tune Ca2+ entry into neurons and cardiomyocytes. Although known to be initiated by distinct molecular events, how these processes obstruct conduction through the channel pore remains poorly defined. Here, focusing on ultrahighly conserved tryptophan residues in the interdomain interfaces near the selectivity filter of CaV1.3, we demonstrate a critical role for asymmetric conformational changes in mediating VDI and CDI. Specifically, mutagenesis of the domain III-IV interface, but not others, enhanced VDI. Molecular dynamics simulations demonstrate that mutations in distinct selectivity filter interfaces differentially impact conforma

SUBMITTER: Del Rivero Morfin PJ 

PROVIDER: S-EPMC10771039 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature