PT  - JOURNAL ARTICLE
AU  - Jahanshah Amin
TI  - A Single Hydrophobic Residue Confers Barbiturate Sensitivity to γ-Aminobutyric Acid Type C Receptor
DP  - 1999 Mar 01
TA  - Molecular Pharmacology
PG  - 411--423
VI  - 55
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/55/3/411.short
4100  - http://molpharm.aspetjournals.org/content/55/3/411.full
SO  - Mol Pharmacol1999 Mar 01; 55
AB  - Barbiturate sensitivity was imparted to the human ρ1homooligomeric γ-aminobutyric acid (GABA) receptor channel by mutation of a tryptophan residue at position 328 (Trp328), which is located within the third transmembrane domain. Substitutions of Trp328 with a spectrum of amino acids revealed that nearly all hydrophobic residues produced receptor channels that were both directly activated and modulated by pentobarbital with similar sensitivities. Previous studies with ligand-gated ion channels (including GABA) have demonstrated that even conservative amino acid substitution within the agonist-dependent activation domain (N-terminal extracellular domain) can markedly impair agonist sensitivity. Thus, the lack of significant variation in pentobarbital sensitivity among the Trp328 mutants attests to an intrinsic difference between pentobarbital- and the GABA-dependent activation domain. Compared with the heterooligomeric αβγ receptor channel, the mode of modulation for homooligomeric Trp328 mutants by pentobarbital was more dependent on the GABA concentration, yielding potentiation only at low concentrations of GABA (fractions of their respective EC50 values), yet causing inhibition at higher concentrations. Agonist-related studies have also demonstrated that residue 328 plays an important role in agonist-dependent activation, suggesting a functional interconnection between the GABA and pentobarbital activation domains. The American Society for Pharmacology and Experimental Therapeutics