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Vol. 55, Issue 3, 411-423, March 1999
-Aminobutyric Acid Type C Receptor
Department of Pharmacology and Therapeutics and The Institute for
Biomolecular Science, University of South Florida, College of Medicine,
Tampa, Florida
Barbiturate sensitivity was imparted to the human 
1
homooligomeric 
-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
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.
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