You can also read a paper (without figures) about the Diverse Molecular Mechanisms of Gap Junction Channel Gating by clicking here

Bruce J. Nicholson, Joseph Smith, FengLi Cao and Lan Zhou

It has been proposed that voltage gating of gap junction channels is mediated by a propagated conformational change between transmembrane domains, from M1 (the proposed voltage sensor-Verseilis et al., 1993) to M3 (the proposed pore lining segment - see abstract by Skerrett et al.). Critical to this, in the case of Cx26, is a conserved proline (P87) in M2 (Suchyna et al., 1993), although this site seems to play little role in gating of Cx32 channels. Consistent with a role in directional propagation of a conformational change, the modified gating of Cx26 the P87L mutant is rescued (close to wt behavior) by reintroduction of the proline on exactly the same face of the M2 helix (7 residues to the C-terminus of the original position). Re-introduction of proline in the N-terminal (extracellular) half of M2 failed to produce functional channels, likely reflecting limitations on the tertiary structure of the extracellular docking domains. We further provide evidence that the different effects of proline substitution in Cx32 and Cx26 reflect a fundamental difference in the gating mechanisms of connexins that respond to negative polarities of Vj (i.e. Cx32 and 45) and those that respond to positive Vj polarities (i.e. Cx26, 30.3, 37, 40, etc.).

In contrast to the "global conformational change" implicated in voltage gating, pH and v-src induced closure of Cx43 channels appear to occur through discrete interactions between the C-terminal domain and the channel mouth (analagous to the "ball and chain" inactivation of K⁺ channels). The domains that are responsive to these latter two effects are distinct, but overlapping, involving residues 240-280 for v-src (Zhou et al., 1999), and residues 260-300 and 374-382 for pH (Ek-Vitorin et al., 1996). In both types of gating, it appears that other factors are involved. In the case of v-src, direct phosphorylation and binding were not found to influence acute gating, which is in fact mediated by the indirect activation of MAPKinase. Consistent with addition of phosphates to the C-terminus being a trigger for the gating, we have now found that gating kinetics are voltage dependent. This has also allowed us to demonstrate that the kinetics of block are dependent on the concentration of the C-terminal domain when added as a separate peptide, providing definitive proof of the "ball and chain" mechanism of gating in gap. In the case of pH gating, we have utilized a perfused oocyte system to show that pH gating requires a heat sensitive accessory factor(s) present in the oocyte cytoplasm. Addition of a crude oocyte extract restores pH gating in the perfused system to the same sensitivity seen in intact cells.