β subunits of GABAA receptors form proton-gated chloride channels: Insights into the molecular basis

Gamma-aminobutyric acid type A receptors (GABA(A)Rs) are ligand gated channels mediating inhibition in the central nervous system. Here, we identify a so far undescribed function of beta-subunit homomers as proton-gated anion channels. Mutation of a single H267A in beta 3 subunits completely abolishes channel activation by protons. In molecular dynamic simulations of the beta 3 crystal structure protonation of H267 increased the formation of hydrogen bonds between H267 and E270 of the adjacent subunit leading to a pore stabilising ring formation and accumulation of Cl- within the transmembrane pore. Conversion of these residues in proton insensitive rho 1 subunits transfers proton-dependent gating, thus highlighting the role of this interaction in proton sensitivity. Activation of chloride and bicarbonate currents at physiological pH changes (pH(50) is in the range 6- 6.3) and kinetic studies suggest a physiological role in neuronal and non-neuronal tissues that express beta subunits, and thus as potential novel drug target. Beta subunits of GABAA receptors are unexpectedly shown to form homomeric proton gated ion channels attributable to a single histidine residue.

Automated summary

The beta subunits of GABAA receptors can form homomeric proton-gated ion channels, which have not been previously described. The activation of these channels is mediated by a single histidine residue, and it is associated with chloride and bicarbonate currents in neuronal and non-neuronal tissues, suggesting a physiological role and potential as a drug target.