A partial structure for the gamma-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.
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 GABAA receptor, an approach justified by the superfamily relationship of the two receptors [(1987) Nature 328, 221-227]. The model predicts successfully 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 gamma-aminobutyric acid (GABAA) 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 GABAA receptor alpha- and beta-subunits reveal at least 4 reasonably homologous sequences. The relationship between AEP and GABAA receptor leads to the idea that the chloride/bicarbonate channel may be the ancestor of all ligand-gated channels, with ligand gating by gamma-aminobutyric acid and acetylcholine arising later in evolution.
Kosower
E M
EM
Biophysical Organic Chemistry Unit, School of Chemistry, Sackler Faculty of Exact Sciences, Tel-Aviv University, Israel.
D000595:Amino Acid Sequence; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
D001457:Anion Exchange Protein 1, Erythrocyte; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic