A partial structure for the γ‐aminobutyric acid (GABAA) receptor is derived from the model for the nicotinic acetylcholine receptor The anion‐exchange protein of cell membranes is related to the GABAA receptor

Abstract

Based on the nicotinic acetylcholine receptor model [(1987) Eur. J. Biochem. 168, 431–449], a partial model is constructed for the exobilayer portion of the GABA_A receptor, an approach justified by the superfamily relationship of the two receptors [(1987) Nature 328, 221–227]. The model predicts succesfully the excess positive charge on interior strands which constitute the ligand-responsive portion of the receptor. Binding to GABA expands the exobilayer portion of the receptor, opening a pathway to a chloride channel. Separate binding sites for antianxiolytics (benzodiazepines) and hypnotics (barbiturates) are suggested, with prolongation of chloride entry projected as a consequence of stabilization of the open form. The anion-exchange protein (AEP) of membranes (band 3 of red blood cell membranes) is similar in some respects to the γ-aminobutyric acid (GABA_A) receptor. Both proteins are inhibited and labeled by diisocyanatostilbenedisulfonate (DIDS), both transport Cl⁻ and HCO⁻ ₃, and both are membrane proteins. Starting with the lysines known to be labeled in band 3 protein, searches of the amino acid sequences of the GABA_A receptor α- and β-subunits reveal at least 4 reasonably homologous sequences. The relationship between AEP and GABA_A receptor leads to the idea that the chloride/bicarbonate channel may be the ancestor of all ligand-gated channels, with ligand gating by γ-aminobutyric acid and acetylcholine arising later in evolution.