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Proper regulation of neurotransmission requires that ligand-activated ion channels remain closed until agonist binds. How channels then open remains poorly understood. Glycine receptor (GlyR) gating is initiated by agonist binding at interfaces between adjacent subunits in the extracellular domain. Aspartate-97, located at the alpha1 GlyR interface, is a conserved residue in the cys-loop receptor superfamily. The mutation of D97 to arginine (D97R) causes spontaneous channel opening, with open and closed dwell times similar to those of maximally activated WT GlyR. Using a model of the N-terminal domain of the alpha1 GlyR, we hypothesized that an arginine-119 residue was forming intersubunit electrostatic bonds with D97. The D97R/R119E charge reversal restored this interaction, stabilizing channels in their closed states. Cysteine substitution shows that this link occurs between adjacent subunits. This intersubunit electrostatic interaction among GlyR subunits thus contributes to the stabilization of the closed channel state, and its disruption represents a critical step in GlyR activation.
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 Beckstead,
Glycine and gamma-aminobutyric acid(A) receptor function is enhanced by inhaled drugs of abuse.
2000,
Pubmed
,
Xenbase Beckstead,
Anesthetic and ethanol effects on spontaneously opening glycine receptor channels.
2002,
Pubmed
,
Xenbase Bertaccini,
Predicting the transmembrane secondary structure of ligand-gated ion channels.
2002,
Pubmed Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed Boileau,
GABA(A) receptor beta 2 Tyr97 and Leu99 line the GABA-binding site. Insights into mechanisms of agonist and antagonist actions.
2002,
Pubmed
,
Xenbase Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed Careaga,
Thermal motions of surface alpha-helices in the D-galactose chemosensory receptor. Detection by disulfide trapping.
1992,
Pubmed Cashin,
Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor.
2007,
Pubmed
,
Xenbase Chakrapani,
Gating dynamics of the acetylcholine receptor extracellular domain.
2004,
Pubmed Crawford,
Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of alpha1 glycine receptors.
2007,
Pubmed
,
Xenbase Grosman,
Mapping the conformational wave of acetylcholine receptor channel gating.
2000,
Pubmed Grudzinska,
The beta subunit determines the ligand binding properties of synaptic glycine receptors.
2005,
Pubmed Grudzinska,
Mutations within the agonist-binding site convert the homomeric alpha1 glycine receptor into a Zn2+-activated chloride channel.
2008,
Pubmed
,
Xenbase Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed Jha,
Acetylcholine receptor gating at extracellular transmembrane domain interface: the cys-loop and M2-M3 linker.
2007,
Pubmed Kash,
Charged residues in the beta2 subunit involved in GABAA receptor activation.
2004,
Pubmed Kash,
Coupling of agonist binding to channel gating in the GABA(A) receptor.
2003,
Pubmed Kloda,
Agonist-, antagonist-, and benzodiazepine-induced structural changes in the alpha1 Met113-Leu132 region of the GABAA receptor.
2007,
Pubmed
,
Xenbase Langosch,
Conserved quaternary structure of ligand-gated ion channels: the postsynaptic glycine receptor is a pentamer.
1988,
Pubmed Lee,
Principal pathway coupling agonist binding to channel gating in nicotinic receptors.
2005,
Pubmed Lee,
Invariant aspartic Acid in muscle nicotinic receptor contributes selectively to the kinetics of agonist binding.
2004,
Pubmed Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase Miller,
Mapping a molecular link between allosteric inhibition and activation of the glycine receptor.
2008,
Pubmed Mitra,
Dynamics of the acetylcholine receptor pore at the gating transition state.
2005,
Pubmed Purohit,
A stepwise mechanism for acetylcholine receptor channel gating.
2007,
Pubmed Qin,
Hidden Markov modeling for single channel kinetics with filtering and correlated noise.
2000,
Pubmed Qin,
A direct optimization approach to hidden Markov modeling for single channel kinetics.
2000,
Pubmed Rajendra,
The unique extracellular disulfide loop of the glycine receptor is a principal ligand binding element.
1995,
Pubmed Roberts,
Occupancy of a single anesthetic binding pocket is sufficient to enhance glycine receptor function.
2006,
Pubmed
,
Xenbase Schmidt,
Search for allosteric disulfide bonds in NMR structures.
2007,
Pubmed Schofield,
A highly conserved aspartic acid residue in the signature disulfide loop of the alpha 1 subunit is a determinant of gating in the glycine receptor.
2003,
Pubmed Twyman,
Kinetic properties of the glycine receptor main- and sub-conductance states of mouse spinal cord neurones in culture.
1991,
Pubmed Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed Welsh,
Single-channel analysis of ethanol enhancement of glycine receptor function.
2009,
Pubmed
,
Xenbase Xiu,
A unified view of the role of electrostatic interactions in modulating the gating of Cys loop receptors.
2005,
Pubmed
,
Xenbase
