The 70‐year search for the voltage‐sensing mechanism of ion channels

Abstract

This retrospective on the voltage‐sensing mechanisms and gating models of ion channels begins in 1952 with the charged gating particles postulated by Hodgkin and Huxley, viewed as charges moving across the membrane and controlling its permeability to Na+ and K+ ions. Hodgkin and Huxley postulated that their movement should generate small and fast capacitive currents, which were recorded 20 years later as gating currents. In the early 1980s, several voltage‐dependent channels were cloned and found to share a common architecture: four homologous domains or subunits, each displaying six transmembrane α‐helical segments, with the fourth segment (S4) displaying four to seven positive charges invariably separated by two non‐charged residues. This immediately suggested that this segment was serving as the voltage sensor of the channel (the molecular counterpart of the charged gating particle postulated by Hodgkin and Huxley) and led to the development of the sliding helix model. Twenty years later, the X‐ray crystallographic structures of many voltage‐dependent channels allowed investigation of their gating by molecular dynamics. Further understanding of how channels gate will benefit greatly from the acquisition of high‐resolution structures of each of their relevant functional or structural states. This will allow the application of molecular dynamics and other approaches. It will also be key to investigate the energetics of channel gating, permitting an understanding of the physical and molecular determinants of gating. The use of multiscale hierarchical approaches might finally prove to be a rewarding strategy to overcome the limits of the various single approaches to the study of channel gating.

Activation-pathway transitions in human voltage-gated proton channels revealed by a non-canonical fluorescent amino acid

“…Voltage-gated, proton-permeable ion currents in a large variety of cell types and organisms are produced by the H V 1 gene (HVCN1 in humans), which encodes a membrane protein that is a member of the superfamily of voltage-sensing domains (VSDs; Sasaki et al, 2006 ; Ramsey et al, 2006 ). These VSDs are also encountered in voltage-sensitive phosphatases (VSPs) and voltage-gated ion channels (VGICs), and their principal function is to detect the membrane potential difference and translate it into a conformational change that activates VSP and opens VGIC ( Catacuzzeno and Franciolini, 2022 ).…”

Neurobiological reduction: From cellular explanations of behavior to interventions

“…One obvious benefit of reductive analyses is to provide detail that can inform and constrain higher-level abstract or phenomenological models. Hodgkin and Huxley (1952 , p. 541) cautioned their action potential model, “must not be taken as evidence that our equations are anything more than an empirical description…An equally satisfactory description of the voltage clamp data could no doubt have been achieved with equations of very different form”: their model was ultimately supported by molecular analyses of channel properties over three decades later ( Catacuzzeno and Franciolini, 2022 ).…”

Conformations and Currents Make the Nerve Signal

“…Direct computation is essentially impossible, as should be obvious to anyone who has numerically integrated differential equations for even thousands of time steps and compared the result to known analytical results. Such comparisons are conspicuously absent in the literature of molecular dynamics of proteins or ionic solutions 4 , despite the ~10 11 time steps needed to reach biological time scales. [85] Hierarchy of scales is an essential part of biology.…”

“…One place these questions can be (mostly) answered is in the proteins that form the voltage activated sodium channel of nerve, the ion channel NaV and the voltage activated potassium channel of nerve KV. [4] These channels are responsible for signaling in the nervous system. Conformation changes of these channels on the atomic scale produce electrical signals that move meters and carry nearly all long range information in the nervous system.…”