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Identification of an Amino Acid Defining the Distinct Properties of Murine β 1 and β 3 Subunit‐Containing GABA A Receptors
Author(s) -
Cestari Ismar N.,
Min Kyeong T.,
Kulli John C.,
Yang Jay
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.740827.x
Subject(s) - homomeric , receptor , allosteric regulation , protein subunit , xenopus , gabaa rho receptor , gabaa receptor , asparagine , biochemistry , chemistry , transmembrane domain , amino acid , cys loop receptors , serine , biology , biophysics , nicotinic agonist , nicotinic acetylcholine receptor , gene , enzyme
Murine γ‐aminobutyric acid (GABA) type A homomeric receptors made of β 1 subunits are profoundly different, when expressed in Xenopus oocytes, from β 3 homomeric receptors. Application of the intravenous general anesthetic pentobarbital, etomidate, or propofol to β 3 homomeric receptors allows current flow. In contrast, β 1 homomers do not respond to any of these agents. Through construction of chimeric β 1 /β 3 receptors, we identified a single amino acid that determines the pharmacological difference between the two β subunits. When the serine residue present in the wild‐type nonresponsive β 1 subunit is replaced by an asparagine found in the same position in the β 3 subunit, the resulting point‐mutated β 1 S265N forms receptors responsive to intravenous general anesthetics, like the wild‐type β 3 subunits. Conversely, after mutation of the wild‐type β 3 to β 3 N265S, the homomeric receptor loses its ability to respond to these same general anesthetics. Wild‐type‐to‐mutant titration experiments showed that the nonresponsive phenotype is dominant: A single nonresponsive residue within a pentameric receptor is sufficient to render the receptor nonresponsive. In α 1 β x or α 1 β x γ 2 heteromeric receptors, the same residue manifests as a partial determinant of the degree of potentiation of the GABA‐induced current by some general anesthetics. The location of this amino acid at the extracellular end of the second transmembrane segment, its influence in both homomeric and heteromeric receptor function, and its dominant behavior suggest that this residue of the β subunit is involved in an allosteric modulation of the receptor.