Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2006 May 01;1482:162-72. doi: 10.1038/sj.bjp.0706719.
Show Gene links
Show Anatomy links
Residues in the first transmembrane domain of the Caenorhabditis elegans GABA(A) receptor confer sensitivity to the neurosteroid pregnenolone sulfate.
Wardell B
,
Marik PS
,
Piper D
,
Rutar T
,
Jorgensen EM
,
Bamber BA
.
???displayArticle.abstract???
The GABA(A) receptor is a target of endogenous and synthetic neurosteroids. Little is known about the residues required for neurosteroid action on GABA(A) receptors. We have investigated pregnenolone sulfate (PS) inhibition of the Caenorhabditis elegans UNC-49 GABA receptor, a close homolog of the mammalian GABA(A) receptor. The UNC-49 locus encodes two GABA receptor subunits, UNC-49B and UNC-49C. UNC-49C is sensitive to PS but UNC-49B is not sensitive. By analyzing chimeric receptors and receptors containing site-directed mutations, we identified two regions required for PS inhibition. Four residues in the first transmembrane domain are required for the majority of the sensitivity to PS, but a charged extracellular residue at the end of the M2 helix also plays a role. Strikingly, mutation of one additional M1 residue reverses the effect of PS from an inhibitor to an enhancer of receptor function. Mutating the M1 domain had little effect on sensitivity to the inhibitor picrotoxin, suggesting that these residues may mediate neurosteroid action specifically, and not allosteric regulation in general.
Akk,
Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit.
2001, Pubmed
Akk,
Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit.
2001,
Pubmed
Bamber,
Pharmacological characterization of the homomeric and heteromeric UNC-49 GABA receptors in C. elegans.
2003,
Pubmed
,
Xenbase
Bamber,
The composition of the GABA receptor at the Caenorhabditis elegans neuromuscular junction.
2005,
Pubmed
Bamber,
The Caenorhabditis elegans unc-49 locus encodes multiple subunits of a heteromultimeric GABA receptor.
1999,
Pubmed
,
Xenbase
Belelli,
Neurosteroids: endogenous regulators of the GABA(A) receptor.
2005,
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
Bianchi,
Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAa receptors.
2001,
Pubmed
Carlson,
A single glycine residue at the entrance to the first membrane-spanning domain of the gamma-aminobutyric acid type A receptor beta(2) subunit affects allosteric sensitivity to GABA and anesthetics.
2000,
Pubmed
Chang,
A single M1 residue in the beta2 subunit alters channel gating of GABAA receptor in anesthetic modulation and direct activation.
2003,
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
Dang,
Probing the role of a conserved M1 proline residue in 5-hydroxytryptamine(3) receptor gating.
2000,
Pubmed
,
Xenbase
England,
Backbone mutations in transmembrane domains of a ligand-gated ion channel: implications for the mechanism of gating.
1999,
Pubmed
,
Xenbase
Ffrench-Constant,
A point mutation in a Drosophila GABA receptor confers insecticide resistance.
1993,
Pubmed
,
Xenbase
Gasior,
Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders.
1999,
Pubmed
Jones,
Microscopic kinetics and energetics distinguish GABA(A) receptor agonists from antagonists.
2001,
Pubmed
Kerrigan,
Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial.
2000,
Pubmed
Laxer,
Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group.
2000,
Pubmed
Lester,
Cys-loop receptors: new twists and turns.
2004,
Pubmed
Macdonald,
GABAA receptor channels.
1994,
Pubmed
Majewska,
Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance.
1992,
Pubmed
Mellon,
Neurosteroids: biochemistry and clinical significance.
2002,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Morris,
Insight into the mechanism of action of neuroactive steroids.
2004,
Pubmed
,
Xenbase
Nilsson,
Neurosteroid analogues. 6. The synthesis and GABAA receptor pharmacology of enantiomers of dehydroepiandrosterone sulfate, pregnenolone sulfate, and (3alpha,5beta)-3-hydroxypregnan-20-one sulfate.
1998,
Pubmed
Olsen,
Molecular biology of GABAA receptors.
1990,
Pubmed
Park-Chung,
Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites.
1999,
Pubmed
,
Xenbase
Paul,
Neuroactive steroids.
1992,
Pubmed
Rajendra,
Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists.
1995,
Pubmed
Rupprecht,
Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties.
2003,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Shen,
Pregnenolone sulfate and dehydroepiandrosterone sulfate inhibit GABA-gated chloride currents in Xenopus oocytes expressing picrotoxin-insensitive GABA(A) receptors.
1999,
Pubmed
,
Xenbase
Thompson,
CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.
1994,
Pubmed
Vallée,
Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus.
1997,
Pubmed
Wu,
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.
1991,
Pubmed
Zaman,
Effects of subunit types of the recombinant GABAA receptor on the response to a neurosteroid.
1992,
Pubmed
,
Xenbase
