Opposing modulation of Cx26 gap junctions and hemichannels by CO₂

Abstract

A moderate increase in P CO 2 (55 mmHg) closes Cx26 gap junctions. r This effect of CO 2 is independent of changes in intra-or extracellular pH. r The CO 2-dependent closing effect depends on the same residues (K125 and R104) that are required for the CO 2-dependent opening of Cx26 hemichannels. r Pathological mutations of Cx26 abolish the CO 2-dependent closing of the gap junction. r Elastic network modelling suggests that the effect of CO 2 on Cx26 hemichannels and gap junctions is mediated through changes in the lowest entropy state of the protein.

Conformational changes and CO2-induced channel gating in connexin26

“…. In cells, an increase in PCO 2 causes gap junctions to close (Nijjar et al, 2021). In our analysis, we observe that the most constricted pore is seen at the highest level of PCO 2 , which is in broad agreement with the results in cells.…”

Carbon Dioxide and the Carbamate Post-Translational Modification

“…Recent work by Nijjar et al, 2020 has shown in contrast to the opening of HCs at high physiological CO 2 that intact Cx26 GJs connecting HeLa cells are closed when pCO 2 is increased from 35 to 55 mmHg. This closing effect is dependent on the same residues (K125 and R104) involved in the CO 2 -dependant opening of Cx26 hemichannels.…”

“…Further, the action is also directly attributed to a change in pCO 2 rather than to changes in pH. They explained the contrasting action based on the free energy difference between CO 2 -bound and unbound states for HC and GJ ( Nijjar et al, 2020 ). Specifically, it was energetically more favourable for HCs to bind CO 2 in the open state and less energetically unfavourable to close.…”

“…The docking of two connexons as an HC provided a close interaction that constrained the conformation of hemichannels docked in a gap junction. Niijar et al, 2020 proposed the need for more information about the structures of Cx26 as free HCs and as components of GJs to investigate conformational differences and provide a greater understanding of the differential modulation of hemichannels and gap junctions by CO 2 . What is clear from these studies is that CO 2 can have a signalling role via carbamate formation.…”

CO2-Sensitive Connexin Hemichannels in Neurons and Glia: Three Different Modes of Signalling?

“…Recently, CO 2 has been found to close Cx26 gap junctions. This closing action of CO 2 on the gap junctions shows a similar dependence on K125 and R104 to the hemichannel opening [ 24 ]. Interestingly, gap junctions of Cx32 are insensitive to CO 2 , indicating that the actions of CO 2 on the connexins have considerable complexity.…”