Asymmetric Contribution of a Selectivity Filter Gate in Triggering Inactivation of Ca_V1.3 Channels.

ABSTRACT: Voltage-dependent and Ca²⁺-dependent inactivation (VDI and CDI, respectively) of Ca_V 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 ultra-highly conserved tryptophan residues in the inter-domain interfaces near the selectivity filter of Ca_V1.3, 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 fi

SUBMITTER: Del Rivero Morfin PJ 

PROVIDER: S-EPMC10542529 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature