Structural determinants of voltage-gating properties in calcium channels

eLife

Klaus R Liedl¹  Petronel Tuluc²  Yousra El Ghaleb³  Marta Campiglio³  Bernhard E Flucher³  Monica L Fernández-Quintero⁴ 

[1] Department of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria;Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria;Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria;Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria;Department of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria;

关键词: Ca1.1;    voltage sensing;    voltage-gated calcium channel;    resting state structure;    molecular dynamics simulation;    Mouse;   

DOI  :  10.7554/eLife.64087

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Voltage-gated calcium channels control key functions of excitable cells, like synaptic transmission in neurons and the contraction of heart and skeletal muscles. To accomplish such diverse functions, different calcium channels activate at different voltages and with distinct kinetics. To identify the molecular mechanisms governing specific voltage sensing properties, we combined structure modeling, mutagenesis, and electrophysiology to analyze the structures, free energy, and transition kinetics of the activated and resting states of two functionally distinct voltage sensing domains (VSDs) of the eukaryotic calcium channel CaV1.1. Both VSDs displayed the typical features of the sliding helix model; however, they greatly differed in ion-pair formation of the outer gating charges. Specifically, stabilization of the activated state enhanced the voltage dependence of activation, while stabilization of resting states slowed the kinetics. This mechanism provides a mechanistic model explaining how specific ion-pair formation in separate VSDs can realize the characteristic gating properties of voltage-gated cation channels.

【 授权许可】

CC BY