Williams DB (2011), A mutant residue in the third transmembrane reg...

XB-ART-42876

Neurochem Int 2011 Jun 01;587:794-803. doi: 10.1016/j.neuint.2011.03.005.

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A mutant residue in the third transmembrane region of the GABA(A) alpha1 subunit causes increased agonistic neurosteroid responses.

Williams DB .

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Pregnane derived steroids have agonistic and antagonistic actions at GABA(A) receptors. Putative binding sites for agonistic neurosteroids are located within the transmembrane (TM) regions. A mutation within the rat α(1) TM3 region, S299C, caused the expressed receptors to have unusual and extreme sensitivity to agonistic neurosteroids. For mutant α1S299C receptors, with wild type β and γ subunits, expressed in Xenopus oocytes, steroids activated the GABA(A) receptors in the absence of GABA. Maximal steroid induced currents were about half of maximal GABA currents. The steroid activation was biphasic with EC(50)'s much lower than wild type, in subnanomolar and nanomolar concentrations, while the wild type had only one activation peak with near micromolar EC(50). These currents could be blocked by both picrotoxin and an antagonist neurosteroid. The steroids did not seem to potentiate significantly submaximal GABA currents. The α1S299C mutation did not affect responses to the extracellularly acting partial agonist piperidine-4-sulfate. Substituted cysteine experiments indicate that this mutant can be modified by pCMBS(-) when the sulfhydryl reagent is added with the higher steroid concentration for activation but not the lower steroid concentration. The pCMBS(-) will also immediately block the high concentration steroid current. Taken together the data suggest that α1S299 is important in at least the in transduction of the steroid binding to the rest of the receptor.

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Species referenced: Xenopus laevis
Genes referenced: tpm3

References [+] :

Akk, Neuroactive steroids have multiple actions to potentiate GABAA receptors. 2004, Pubmed

Akk, Neuroactive steroids have multiple actions to potentiate GABAA receptors. 2004, Pubmed
Akk, Neurosteroid access to the GABAA receptor. 2005, Pubmed
Akk, Mechanisms of neurosteroid interactions with GABA(A) receptors. 2007, Pubmed
Akk, Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids. 2008, Pubmed
Akk, The influence of the membrane on neurosteroid actions at GABA(A) receptors. 2009, 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
Amin, GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital. 1993, Pubmed , Xenbase
Bai, The general anesthetic propofol slows deactivation and desensitization of GABA(A) receptors. 1999, Pubmed
Baker, Multiple roles for the first transmembrane domain of GABAA receptor subunits in neurosteroid modulation and spontaneous channel activity. 2010, Pubmed
Bali, Defining the propofol binding site location on the GABAA receptor. 2004, Pubmed , Xenbase
Bali, GABA-induced intersubunit conformational movement in the GABAA receptor alpha 1M1-beta 2M3 transmembrane subunit interface: experimental basis for homology modeling of an intravenous anesthetic binding site. 2009, Pubmed , Xenbase
Boileau, Identification of transduction elements for benzodiazepine modulation of the GABA(A) receptor: three residues are required for allosteric coupling. 1999, Pubmed , Xenbase
Galvez-Ruano, Identifying agonistic and antagonistic mechanisms operative at the GABA receptor. 1995, Pubmed
Girdler, Neurosteroids in the context of stress: implications for depressive disorders. 2007, Pubmed
Herd, Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. 2007, Pubmed
Hosie, Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. 2006, Pubmed
Hosie, Neurosteroid binding sites on GABA(A) receptors. 2007, Pubmed
Hosie, Conserved site for neurosteroid modulation of GABA A receptors. 2009, Pubmed
Jansen, State-dependent cross-linking of the M2 and M3 segments: functional basis for the alignment of GABAA and acetylcholine receptor M3 segments. 2006, Pubmed , Xenbase
Jones-Davis, Structural determinants of benzodiazepine allosteric regulation of GABA(A) receptor currents. 2005, Pubmed
Keramidas, The pre-M1 segment of the alpha1 subunit is a transduction element in the activation of the GABAA receptor. 2006, Pubmed
Krogsgaard-Larsen, Piperidine-4-sulphonic acid, a new specific GABA agonist. 1980, Pubmed
Li, Dual potentiating and inhibitory actions of a benz[e]indene neurosteroid analog on recombinant alpha1beta2gamma2 GABAA receptors. 2006, Pubmed
Li, Neurosteroids allosterically modulate binding of the anesthetic etomidate to gamma-aminobutyric acid type A receptors. 2009, Pubmed
Liu, Allopregnanolone activates GABA(A) receptor/Cl(-) channels in a multiphasic manner in embryonic rat hippocampal neurons. 2002, Pubmed
Longone, The complex roles of neurosteroids in depression and anxiety disorders. 2008, Pubmed
Marx, Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. 2006, Pubmed
Mennerick, Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors. 2004, Pubmed , Xenbase
Mihic, Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. 1997, Pubmed , Xenbase
Paul, Neuroactive steroids. 1992, Pubmed
Puia, On the putative physiological role of allopregnanolone on GABA(A) receptor function. 2003, Pubmed
Rick, Neurosteroids act on the GABA(A) receptor at sites on the N-terminal side of the middle of TM2. 1998, Pubmed
Schlichter, Fast nongenomic effects of steroids on synaptic transmission and role of endogenous neurosteroids in spinal pain pathways. 2006, Pubmed
Shu, Slow actions of neuroactive steroids at GABAA receptors. 2004, Pubmed , Xenbase
Twede, The neurosteroids dehydroepiandrosterone sulfate and pregnenolone sulfate inhibit the UNC-49 GABA receptor through a common set of residues. 2007, Pubmed , Xenbase
Twyman, Neurosteroid regulation of GABAA receptor single-channel kinetic properties of mouse spinal cord neurons in culture. 1992, Pubmed
Ueno, Sites of positive allosteric modulation by neurosteroids on ionotropic gamma-aminobutyric acid receptor subunits. 2004, Pubmed , Xenbase
Wang, 3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists. 2002, Pubmed , Xenbase
Wardell, Residues in the first transmembrane domain of the Caenorhabditis elegans GABA(A) receptor confer sensitivity to the neurosteroid pregnenolone sulfate. 2006, Pubmed , Xenbase
Whiting, GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery? 2003, Pubmed
Williams, A novel, rapid, inhibitory effect of insulin on alpha1beta2gamma2s gamma-aminobutyric acid type A receptors. 2008, Pubmed , Xenbase
Williams, Gamma-aminobutyric acid increases the water accessibility of M3 membrane-spanning segment residues in gamma-aminobutyric acid type A receptors. 1999, Pubmed
Williams, Benzodiazepines induce a conformational change in the region of the gamma-aminobutyric acid type A receptor alpha(1)-subunit M3 membrane-spanning segment. 2000, Pubmed , Xenbase
Williams, Evidence for distinct conformations of the two alpha 1 subunits in diazepam-bound GABA(A) receptors. 2001, Pubmed , Xenbase
Williams, Structural evidence that propofol stabilizes different GABA(A) receptor states at potentiating and activating concentrations. 2002, Pubmed , Xenbase
Yevenes, Molecular requirements for ethanol differential allosteric modulation of glycine receptors based on selective Gbetagamma modulation. 2010, Pubmed
Zhu, Neurosteroid prolongs GABAA channel deactivation by altering kinetics of desensitized states. 1997, Pubmed