A Gating Lever and Molecular Logic Gate That Couple Voltage and Calcium Sensor Activation to Opening in BK Potassium Channels

Authors

Liang Sun
Frank T Horrigan

Publication Date

12-14-2022

Journal

Science Advances

DOI

10.1126/sciadv.abq5772

PMID

36516264

PMCID

PMC9750137

PubMedCentral® Posted Date

12-14-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Abstract

BK channels uniquely integrate voltage and calcium signaling in diverse cell types through allosteric activation of their K+-conducting pore by structurally distinct V and Ca2+ sensor domains. Here, we define mechanisms and interaction pathways that link V sensors to the pore by analyzing effects on allosteric coupling of point mutations in the context of Slo1 BK channel structure. A gating lever, mediated by S4/S5 segment interaction within the transmembrane domain, rotates to engage and stabilize the open conformation of the S6 inner pore helix upon V sensor activation. In addition, an indirect pathway, mediated by the carboxyl-terminal cytosolic domain (CTD) and C-linker that connects the CTD to S6, stabilizes the closed conformation when V sensors are at rest. Unexpectedly, this mechanism, which bypasses the covalent connections of C-linker to CTD and pore, also transduces Ca2+-dependent coupling in a manner that is completely nonadditive with voltage, analogous to the function of a digital logic (OR) gate.