γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The GABA receptor type C (GABAC) is a ligand-gated ion channel with pharmacological properties distinct from the GABAA receptor. To date, only three binding domains in the recombinant ρ1 GABAC receptor have been recognized among six potential regions. In this report, using the substituted cysteine accessibility method, we scanned three potential regions previously unexplored in the ρ1 GABAC receptor, corresponding to the binding loops A, E, and F in the structural model for ligand-gated ion channels. The cysteine accessibility scanning and agonist/antagonist protection tests have resulted in the identification of residues in loops A and E, but not F, involved in forming the GABAC receptor agonist binding pocket. Three of these newly identified residues are in a novel region corresponding to the extended stretch of loop E. In addition, the cysteine accessibility pattern suggests that part of loop A and part of loop E have a β-strand structure, whereas loop F is a random coil. Finally, when all of the identified ligand binding residues are mapped onto a three-dimensional homology model of the amino-terminal domain of the ρ1 GABAC receptor, they are facing toward the putative binding pocket. Combined with previous findings, a complete model of the GABAC receptor binding pocket was proposed and discussed in comparison with the GABAA receptor binding pocket.
Journal of Biological Chemistry
Digital Object Identifier (DOI)
Sedelnikova, Anna; Smith, Craig D.; Zakharkin, Stanislav O.; Davis, Delores; Weiss, David S.; and Chang, Yongchang, "Mapping the ρ1 GABAC Receptor Agonist Binding Pocket" (2005). Translational Neuroscience. 58.