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J Pharmacol Exp Ther
2012 Feb 01;3402:304-16. doi: 10.1124/jpet.111.185116.
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Characterization of two mutations, M287L and Q266I, in the α1 glycine receptor subunit that modify sensitivity to alcohols.
Borghese CM
,
Blednov YA
,
Quan Y
,
Iyer SV
,
Xiong W
,
Mihic SJ
,
Zhang L
,
Lovinger DM
,
Trudell JR
,
Homanics GE
,
Harris RA
.
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Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels. Ethanol potentiates glycine activation of the GlyR, and putative binding sites for alcohol are located in the transmembrane (TM) domains between and within subunits. To alter alcohol sensitivity of GlyR, we introduced two mutations in the GlyR α1 subunit, M287L (TM3) and Q266I (TM2). After expression in Xenopus laevis oocytes, both mutants showed a reduction in glycine sensitivity and glycine-induced maximal currents. Activation by taurine, another endogenous agonist, was almost abolished in the M287L GlyR. The ethanol potentiation of glycine currents was reduced in the M287L GlyR and eliminated in Q266I. Physiological levels of zinc (100 nM) potentiate glycine responses in wild-type GlyR and also enhance the ethanol potentiation of glycine responses. Although zinc potentiation of glycine responses was unchanged in both mutants, zinc enhancement of ethanol potentiation of glycine responses was absent in M287L GlyRs. The Q266I mutation decreased conductance but increased mean open time (effects not seen in M287L). Two lines of knockin mice bearing these mutations were developed. Survival of homozygous knockin mice was impaired, probably as a consequence of impaired glycinergic transmission. Glycine showed a decreased capacity for displacing strychnine binding in heterozygous knockin mice. Electrophysiology in isolated neurons of brain stem showed decreased glycine-mediated currents and decreased ethanol potentiation in homozygous knockin mice. Molecular models of the wild-type and mutant GlyRs show a smaller water-filled cavity within the TM domains of the Q266I α1 subunit. The behavioral characterization of these knockin mice is presented in a companion article (J Pharmacol Exp Ther 340:317-329, 2012).
Alifimoff,
Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site.
1989, Pubmed
Alifimoff,
Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site.
1989,
Pubmed
Becker,
The novel hyperekplexia allele GLRA1(S267N) affects the ethanol site of the glycine receptor.
2008,
Pubmed
Blednov,
Behavioral characterization of knockin mice with mutations M287L and Q266I in the glycine receptor α1 subunit.
2012,
Pubmed
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Boehm,
Deletion of the fyn-kinase gene alters sensitivity to GABAergic drugs: dependence on beta2/beta3 GABAA receptor subunits.
2004,
Pubmed
Breitinger,
Molecular dynamics simulation links conformation of a pore-flanking region to hyperekplexia-related dysfunction of the inhibitory glycine receptor.
2004,
Pubmed
Buckwalter,
A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death.
1994,
Pubmed
Castaldo,
A novel hyperekplexia-causing mutation in the pre-transmembrane segment 1 of the human glycine receptor alpha1 subunit reduces membrane expression and impairs gating by agonists.
2004,
Pubmed
Celentano,
Ethanol potentiates GABA- and glycine-induced chloride currents in chick spinal cord neurons.
1988,
Pubmed
Chung,
Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia.
2010,
Pubmed
Duret,
Functional prokaryotic-eukaryotic chimera from the pentameric ligand-gated ion channel family.
2011,
Pubmed
,
Xenbase
Ernst,
Comparative models of GABAA receptor extracellular and transmembrane domains: important insights in pharmacology and function.
2005,
Pubmed
Findlay,
Glycine receptor knock-in mice and hyperekplexia-like phenotypes: comparisons with the null mutant.
2003,
Pubmed
,
Xenbase
Findlay,
Transgenic expression of a mutant glycine receptor decreases alcohol sensitivity of mice.
2002,
Pubmed
,
Xenbase
Graham,
Altered inhibitory synaptic transmission in superficial dorsal horn neurones in spastic and oscillator mice.
2003,
Pubmed
Harvey,
The genetics of hyperekplexia: more than startle!
2008,
Pubmed
Hirzel,
Hyperekplexia phenotype of glycine receptor alpha1 subunit mutant mice identifies Zn(2+) as an essential endogenous modulator of glycinergic neurotransmission.
2006,
Pubmed
Homanics,
Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics.
1997,
Pubmed
Howard,
Structural basis for alcohol modulation of a pentameric ligand-gated ion channel.
2011,
Pubmed
,
Xenbase
Kling,
The frameshift mutation oscillator (Glra1(spd-ot)) produces a complete loss of glycine receptor alpha1-polypeptide in mouse central nervous system.
1997,
Pubmed
Langosch,
Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia.
1994,
Pubmed
,
Xenbase
Liu,
Allosteric potentiation of glycine receptor chloride currents by glutamate.
2010,
Pubmed
Lobo,
Cross-linking of sites involved with alcohol action between transmembrane segments 1 and 3 of the glycine receptor following activation.
2008,
Pubmed
,
Xenbase
Lynch,
Native glycine receptor subtypes and their physiological roles.
2009,
Pubmed
Mascia,
A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors.
1996,
Pubmed
,
Xenbase
Mascia,
Specific binding sites for alcohols and anesthetics on ligand-gated ion channels.
2000,
Pubmed
,
Xenbase
McCracken,
Linking of Glycine Receptor Transmembrane Segments Three and Four Allows Assignment of Intrasubunit-Facing Residues.
2010,
Pubmed
,
Xenbase
McCracken,
Zinc enhances ethanol modulation of the alpha1 glycine receptor.
2010,
Pubmed
,
Xenbase
Meyers,
An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination.
1998,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Moorhouse,
The startle disease mutation Q266H, in the second transmembrane domain of the human glycine receptor, impairs channel gating.
1999,
Pubmed
Nagy,
Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.
1993,
Pubmed
Plested,
Single-channel study of the spasmodic mutation alpha1A52S in recombinant rat glycine receptors.
2007,
Pubmed
Ponder,
Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequences for different structural classes.
1987,
Pubmed
Rajendra,
Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists.
1995,
Pubmed
Rodríguez,
High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP.
2000,
Pubmed
Saul,
Point mutation of glycine receptor alpha 1 subunit in the spasmodic mouse affects agonist responses.
1994,
Pubmed
,
Xenbase
Trudell,
Are sobriety and consciousness determined by water in protein cavities?
2004,
Pubmed
Villmann,
Recessive hyperekplexia mutations of the glycine receptor alpha1 subunit affect cell surface integration and stability.
2009,
Pubmed
Welsh,
Single-channel analysis of ethanol enhancement of glycine receptor function.
2009,
Pubmed
,
Xenbase
Werner,
Inhaled anesthetic responses of recombinant receptors and knockin mice harboring α2(S270H/L277A) GABA(A) receptor subunits that are resistant to isoflurane.
2011,
Pubmed
,
Xenbase
White,
Glycine receptor alteration in the mutant mouse spastic.
1982,
Pubmed
