Voltage-dependent conformational changes in connexin channels

Abstract

Channels formed by connexins display two distinct types of voltage-dependent gating, termed Vj- or fast-gating and loop- or slow-gating. Recent studies, using metal bridge formation and chemical cross-linking have identified a region within the channel pore that contributes to the formation of the loop-gate permeability barrier. The conformational changes are remarkably large, reducing the channel pore diameter from 15 to 20 Å to less than 4 Å. Surprisingly, the largest conformational change occurs in the most stable region of the channel pore, the 310 or parahelix formed by amino acids in the 42–51 segment. The data provide a set of positional constraints that can be used to model the structure of the loop-gate closed state. Less is known about the conformation of the Vj-gate closed state. There appear to be two different mechanisms; one in which conformational changes in channel structure are linked to a voltage sensor contained in the N-terminus of Cx26 and Cx32 and a second in which the C-terminus of Cx43 and Cx40 may act either as a gating particle to block the channel pore or alternatively to stabilize the closed state. The later mechanismutilizes the same domains as implicated in effecting pH gating of Cx43 channels. It is unclear if the two Vj-gating mechanisms are related or if they represent different gating mechanisms that operate separately in different subsets of connexin channels. A model of the Vj-closed state of Cx26 hemichannel that is based on the X-ray structure of Cx26 and electron crystallographic structures of a Cx26 mutation suggests that the permeability barrier for Vj-gating is formed exclusively by the N-terminus, but recent information suggests that this conformation may not represent a voltage-closed state. Closed state models are considered from a thermodynamic perspective based on information from the 3.5 Å Cx26 crystal structure and molecular dynamics (MD) simulations. The applications of computational and experimental methods to define the path of allosteric molecular transitions that link the open and closed states are discussed. This article is part of a Special Issue entitled: The communicating junctions, composition, structure and functions.

Cataract-associated connexin 46 mutation alters its interaction with calmodulin and function of hemichannels

“…Two mechanisms have been proposed for voltage gating of gap junction channels; one is through conformational changes of a voltage sensor located in the N-terminus and the second is through the C-terminus acting as a gating particle to block channel pore or stabilize the closed state (35). A recent study has shown that voltage-dependence of the slow gate is located at charged residues of the first-transmembrane region of Cx46 as well as Cx26 and Cx50 (36).…”

Pannexin 1, an ATP Release Channel, Is Activated by Caspase Cleavage of Its Pore-associated C-terminal Autoinhibitory Region

“…In more closely related connexin channels, the pH modulation of Cx47 (20,21) and fast transjunctional voltage (Vj)-dependent gating of Cx40 and Cx43 (22,23) have also been characterized as a ball-and-chain mechanism. In these cases, this type of mechanism was supported by showing that an isolated ball region could rescue inactivation, pH sensitivity, or Vj-dependent gating in truncated channels (24,25).…”

Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure

“…These results suggest that the charge selectivity of a connexin hemichannel is determined by charges dispersed over the permeation pathway (including several charged residues in the NT). (Some of these and related studies are described in more detail in the accompanying article by Bargiello [34]. )…”