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Identification of transduction elements for benzodiazepine modulation of the GABA(A) receptor: three residues are required for allosteric coupling.
Boileau AJ, Czajkowski C.
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Modulation of GABA(A) receptors by benzodiazepines (BZDs) is believed to involve two distinct steps: a recognition step in which BZDs bind and a conformational transition step in which the affinity of the receptor for GABA changes. Previously, using gamma(2)/alpha(1) chimeric subunits (chi), we demonstrated that although the N-terminal 167 gamma(2) amino acid residues confer high-affinity BZD binding, other gamma(2) domains couple BZD binding to potentiation of the GABA-mediated Cl(-) current (I(GABA)). To determine which gamma(2) regions couple binding to potentiation, we generated chis with longer N-terminal gamma(2) segments for voltage-clamp experiments in Xenopus oocytes. Chimeras containing greater than the N-terminal 167 gamma(2) residues showed incremental gains in maximal potentiation for diazepam enhancement of I(GABA). Residues in gamma(2)199-236, gamma(2)224-236 (pre-M1), and particularly gamma(2)257-297 (M2 and surrounding loops) are important for BZD potentiation. For several positive BZD modulators tested, the same regions restored potentiation of I(GABA). In contrast, beta-carboline inverse-agonism was unaltered in chimeric receptors, suggesting that structural determinants for positive and negative BZD allosteric modulation are different. Dissection of the gamma(2)257-297 domain revealed that three residues in concert, gamma(2)T281, gamma(2)I282 (M2 channel vestibule), and gamma(2)S291 (M2-M3 loop) are necessary to impart full BZD potentiation to chimeric receptors. Thus, these residues participate in coupling distant BZD-binding events to conformational changes in the GABA(A) receptor. The location of these novel residues provides insight into the mechanisms underlying allosteric coupling for other members of the ligand-gated ion channel superfamily.
Amin,
Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acidA receptors.
1997, Pubmed,
Xenbase
Amin,
Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acidA receptors.
1997,
Pubmed
,
Xenbase Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998,
Pubmed Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase Boileau,
Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric gamma-aminobutyric acidA receptor subunits.
1998,
Pubmed
,
Xenbase Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed Czajkowski,
Negatively charged amino acid residues in the nicotinic receptor delta subunit that contribute to the binding of acetylcholine.
1993,
Pubmed
,
Xenbase Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase Lynch,
Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel.
1997,
Pubmed Mihic,
A single amino acid of the human gamma-aminobutyric acid type A receptor gamma 2 subunit determines benzodiazepine efficacy.
1994,
Pubmed
,
Xenbase Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase MONOD,
ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.
1965,
Pubmed Ortells,
Evolutionary history of the ligand-gated ion-channel superfamily of receptors.
1995,
Pubmed Rajendra,
Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists.
1995,
Pubmed Robertson,
Potassium currents expressed from Drosophila and mouse eag cDNAs in Xenopus oocytes.
1996,
Pubmed
,
Xenbase Rogers,
Benzodiazepine and beta-carboline regulation of single GABAA receptor channels of mouse spinal neurones in culture.
1994,
Pubmed Sieghart,
Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.
1995,
Pubmed Sigel,
The benzodiazepine binding site of GABAA receptors.
1997,
Pubmed Smith,
Functional domains of GABAA receptors.
1995,
Pubmed Thompson,
Residues in transmembrane domains I and II determine gamma-aminobutyric acid type AA receptor subtype-selective antagonism by furosemide.
1999,
Pubmed
,
Xenbase Tierney,
Effects of mutating leucine to threonine in the M2 segment of alpha1 and beta1 subunits of GABAA alpha1beta1 receptors.
1996,
Pubmed Wingrove,
The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.
1994,
Pubmed
,
Xenbase Xu,
Identification of channel-lining residues in the M2 membrane-spanning segment of the GABA(A) receptor alpha1 subunit.
1996,
Pubmed
,
Xenbase
