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J Neurosci
2006 Feb 15;267:2031-40. doi: 10.1523/JNEUROSCI.4555-05.2006.
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Charged residues in the alpha1 and beta2 pre-M1 regions involved in GABAA receptor activation.
Mercado J
,
Czajkowski C
.
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For Cys-loop ligand-gated ion channels (LGIC), the protein movements that couple neurotransmitter binding to channel gating are not well known. The pre-M1 region, which links the extracellular agonist-binding domain to the channel-containing transmembrane domain, is in an ideal position to transduce binding site movements to gating movements. A cluster of cationic residues in this region is observed in all LGIC subunits, and in particular, an arginine residue is absolutely conserved. We mutated charged pre-M1 residues in the GABAA receptor alpha1 (K219, R220, K221) and beta2 (K213, K215, R216) subunits to cysteine and expressed the mutant subunits with wild-type beta2 or alpha1 in Xenopus oocytes. Cysteine substitution of beta2R216 abolished channel gating by GABA without altering the binding of the GABA agonist [3H]muscimol, indicating that this residue plays a key role in coupling GABA binding to gating. Tethering thiol-reactive methanethiosulfonate (MTS) reagents onto alpha1K219C, beta2K213C, and beta2K215C increased maximal GABA-activated currents, suggesting that structural perturbations of the pre-M1 regions affect channel gating. GABA altered the rates of sulfhydryl modification of alpha1K219C, beta2K213C, and beta2K215C, indicating that the pre-M1 regions move in response to channel activation. A positively charged MTS reagent modified beta2K213C and beta2K215C significantly faster than a negatively charged reagent, and GABA activation eliminated modification of beta2K215C by the negatively charged reagent. Overall, the data indicate that the pre-M1 region is part of the structural machinery coupling GABA binding to gating and that the transduction of binding site movements to channel movements is mediated, in part, by electrostatic interactions.
Absalom,
Role of charged residues in coupling ligand binding and channel activation in the extracellular domain of the glycine receptor.
2003, Pubmed
Absalom,
Role of charged residues in coupling ligand binding and channel activation in the extracellular domain of the glycine receptor.
2003,
Pubmed
Amin,
GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital.
1993,
Pubmed
,
Xenbase
Boileau,
Mapping the agonist binding site of the GABAA receptor: evidence for a beta-strand.
1999,
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
Boileau,
Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric gamma-aminobutyric acidA receptor subunits.
1998,
Pubmed
,
Xenbase
Bouzat,
Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel.
2004,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
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
Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed
Chakrapani,
Gating dynamics of the acetylcholine receptor extracellular domain.
2004,
Pubmed
Cheung,
Locating the anion-selectivity filter of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel.
1997,
Pubmed
Cromer,
Anxiety over GABA(A) receptor structure relieved by AChBP.
2002,
Pubmed
Dennis,
Amino acids of the Torpedo marmorata acetylcholine receptor alpha subunit labeled by a photoaffinity ligand for the acetylcholine binding site.
1988,
Pubmed
Galzi,
Functional significance of aromatic amino acids from three peptide loops of the alpha 7 neuronal nicotinic receptor site investigated by site-directed mutagenesis.
1991,
Pubmed
,
Xenbase
Galzi,
Allosteric transitions of the acetylcholine receptor probed at the amino acid level with a photolabile cholinergic ligand.
1991,
Pubmed
Grosman,
Mapping the conformational wave of acetylcholine receptor channel gating.
2000,
Pubmed
Grosman,
The extracellular linker of muscle acetylcholine receptor channels is a gating control element.
2000,
Pubmed
Gruia,
Molecular dynamics simulation reveals a surface salt bridge forming a kinetic trap in unfolding of truncated Staphylococcal nuclease.
2003,
Pubmed
Henchman,
Ligand-induced conformational change in the alpha7 nicotinic receptor ligand binding domain.
2005,
Pubmed
Holden,
Different residues in the GABA(A) receptor alpha 1T60-alpha 1K70 region mediate GABA and SR-95531 actions.
2002,
Pubmed
,
Xenbase
Hu,
Arginine 222 in the pre-transmembrane domain 1 of 5-HT3A receptors links agonist binding to channel gating.
2003,
Pubmed
Kao,
Identification of the alpha subunit half-cystine specifically labeled by an affinity reagent for the acetylcholine receptor binding site.
1984,
Pubmed
Karlin,
Substituted-cysteine accessibility method.
1998,
Pubmed
Kash,
Coupling of agonist binding to channel gating in the GABA(A) receptor.
2003,
Pubmed
Kash,
Charged residues in the beta2 subunit involved in GABAA receptor activation.
2004,
Pubmed
Laskowski,
AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR.
1996,
Pubmed
Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase
Mishina,
Location of functional regions of acetylcholine receptor alpha-subunit by site-directed mutagenesis.
,
Pubmed
,
Xenbase
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Mukhtasimova,
Initial coupling of binding to gating mediated by conserved residues in the muscle nicotinic receptor.
2005,
Pubmed
Pascual,
State-dependent accessibility and electrostatic potential in the channel of the acetylcholine receptor. Inferences from rates of reaction of thiosulfonates with substituted cysteines in the M2 segment of the alpha subunit.
1998,
Pubmed
,
Xenbase
Rajendra,
The unique extracellular disulfide loop of the glycine receptor is a principal ligand binding element.
1995,
Pubmed
Robertson,
Potassium currents expressed from Drosophila and mouse eag cDNAs in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Ruiz-Gómez,
Localization of the strychnine binding site on the 48-kilodalton subunit of the glycine receptor.
1990,
Pubmed
Schreiber,
Energetics of protein-protein interactions: analysis of the barnase-barstar interface by single mutations and double mutant cycles.
1995,
Pubmed
Sheldahl,
Molecular dynamics on a model for nascent high-density lipoprotein: role of salt bridges.
1999,
Pubmed
Stauffer,
Electrostatic potential of the acetylcholine binding sites in the nicotinic receptor probed by reactions of binding-site cysteines with charged methanethiosulfonates.
1994,
Pubmed
Unwin,
Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the alpha subunits.
2002,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Vandenberg,
Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor alpha subunit form the strychnine-binding site.
1992,
Pubmed
Vandenberg,
Distinct agonist- and antagonist-binding sites on the glycine receptor.
1992,
Pubmed
Vicente-Agullo,
Multiple roles of the conserved key residue arginine 209 in neuronal nicotinic receptors.
2001,
Pubmed
,
Xenbase
Wagner,
Structure and dynamics of the GABA binding pocket: A narrowing cleft that constricts during activation.
2001,
Pubmed
,
Xenbase
Yang,
Probing the outer vestibule of a sodium channel voltage sensor.
1997,
Pubmed
