Distinct moieties underlie biphasic H + gating of connexin43 channels, producing a pH optimum for intercellular communication

• Published in: The FASEB journal Vol. 32; no. 4; p. 1969
• Main Authors: Garciarena, Carolina D, Malik, Akif, Swietach, Pawel, Moreno, Alonso P, Vaughan-Jones, Richard D
• Format: Journal Article
• Language: English
• Published: United States 01.04.2018
• Subjects: Animals; Cell Communication; Connexin 43 - chemistry; Connexin 43 - metabolism; HeLa Cells; Humans; Hydrogen-Ion Concentration; Ion Channel Gating; Mice; Protons; acid–base; gap junctions; brain; electrical synapse; heart
• ISSN: 1530-6860
• DOI: 10.1096/fj.201700876R

Most mammalian cells can intercommunicate via connexin-assembled, gap-junctional channels. To regulate signal transmission, connexin (Cx) channel permeability must respond dynamically to physiological and pathophysiological stimuli. One key stimulus is intracellular pH (pH ), which is modulated by a tissue's metabolic and perfusion status. Our understanding of the molecular mechanism of H gating of Cx43 channels-the major isoform in the heart and brain-is incomplete. To interrogate the effects of acidic and alkaline pH on Cx43 channels, we combined voltage-clamp electrophysiology with pH imaging and photolytic H uncaging, performed over a range of pH values. We demonstrate that Cx43 channels expressed in HeLa or N2a cell pairs are gated biphasically by pH via a process that consists of activation by H ions at alkaline pH and inhibition at more acidic pH . For Cx43 channel-mediated solute/ion transmission, the ensemble of these effects produces a pH optimum, near resting pH . By using Cx43 mutants, we demonstrate that alkaline gating involves cysteine residues of the C terminus and is independent of motifs previously implicated in acidic gating. Thus, we present a molecular mechanism by which cytoplasmic acid-base chemistry fine tunes intercellular communication and establishes conditions for the optimal transmission of solutes and signals in tissues, such as the heart and brain.-Garciarena, C. D., Malik, A., Swietach, P., Moreno, A. P., Vaughan-Jones, R. D. Distinct moieties underlie biphasic H gating of connexin43 channels, producing a pH optimum for intercellular communication.