Molecular Participants in Voltage-Dependent Gating

Abstract

The ion channels underlying action potentials in excitable cells have an approximate four-fold symmetry with each subunit, or homologous domain, surrounding a central permeation pathway (pore) that extends across the lipid bilayer membrane. Each subunit or domain contains a positively charged transmembrane segment, designated the S4 segment, that acts as a sensor of the membrane potential. The pore is lined by a selectivity filter at its external end and the four S6 transmembrane segments over most of its length. The S6 segments converge at their cytoplasmic ends to form the activation gate that opens and closes the pore. In the present work, we discuss the possible role of other putative voltage sensors in the channel, especially the S2 segment, and mechanisms for coupling S4 and S6 movement. Voltage-gated ion channels are responsible for generating action potentials in excitable cells. Understanding how they accomplish this feat has occupied scientists worldwide for the last half century. This quest has been aided by many technological breakthroughs, including the cloning and sequencing of many members of the superfamily of voltage-gated ion channels, which include sodium, potassium, and calcium channels. As a result of a deluge of 'structure-function' studies the main molecular participants in voltage-dependent gating are now established. An ion channel capable of voltage-dependent gating requires three molecular components: a selective permeation pathway (pore) through which privileged ions can diffuse across the membrane, a gate that permits or denies access to this pore, and a voltage sensor that moves in response to changes of membrane potential. A further requirement is that the voltage sensors and gates of the channel must be coupled, so that gates ultimately respond to changes of membrane potential by opening or closing. This article will describe these three molecular participants in voltage-dependent gating and