Structural determinants of voltage-gating properties in calcium channels

Abstract

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.

The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation

“…S2 B ). Thus, using VCF, we demonstrated the existence of fast- and slow-activating Ca V 1.1 VSDs by directly measuring their activation kinetics, a result that confirms the predictions of Feldmeyer et al (1990) based on ionic current recordings and those of the Flucher laboratory ( Fernández-Quintero et al, 2021 ) based on molecular dynamics simulations, which estimated slow and fast activation kinetics for VSD-I and VSD-IV, respectively.…”

Role of High Voltage-Gated Ca2+ Channel Subunits in Pancreatic β-Cell Insulin Release. From Structure to Function

“…Following the membrane depolarization, the S4 segments rotate and slide through the membrane [44][45][46], pulling on the intracellular S4-S5 linker that induces a conformational change of the S5 and S6 domains. The concerted conformational changes in all four repeats result in the opening of the channel pore [42], with each of the four VSDs having an uneven and isoform-specific contribution [23,44,[46][47][48][49][50][51][52][53]. Seven genes encode for the HVCC α 1 subunit isoforms.…”

Enhanced sampling without borders: on global biasing functions and how to reweight them

“…with the aid of machine learning. [24][25][26] Given relevant CVs, pathwaydependent methodologies can perform strikingly well, for example in modelling the activation of voltage-sensing domain of ion channels, 27,28 the estimation of ligand k of f rates, 29 or membrane permeation probability calculations. 30,31 Despite these successes, for many interesting biomolecular systems it is not straight-forward to derive a small number of representative observables as CVs.…”