Molecular mechanisms of inherited startle syndromes

Rajendra, Sundran

doi:10.1016/0166-2236(95)93880-7

Cited by 40 publications

(25 citation statements)

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“…Such a scheme is needed, first of all, for the interpretation of the characteristics of glycinergic synaptic currents, such as the factors that control their time course, degree of postsynaptic receptor saturation, or effects of antagonists on synaptic transmission. Without knowledge of a mechanism, it is also impossible to understand the functional effects of mutations in glycine receptor subunits (for human startle disease mutations, see Rajendra and Schofield, 1995), the nature of the binding site for glycine and other agonists, the process of channel opening, and the link between them (Edmonds et al, 1995;Colquhoun, 1998).…”

Section: Introductionmentioning

confidence: 99%

The Activation Mechanism of α1 Homomeric Glycine Receptors

Beato

Groot-Kormelink²,

Colquhoun³

et al. 2004

J. Neurosci.

103

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The glycine receptor mediates fast synaptic inhibition in the spinal cord and brainstem. Its activation mechanism is not known, despite the physiological importance of this receptor and the fact that it can serve as a prototype for other homopentameric channels. We analyzed single-channel recordings from rat recombinant ␣1 glycine receptors by fitting different mechanisms simultaneously to sets of sequences of openings at four glycine concentrations (10 -1000 M). The adequacy of the mechanism and the rate constants thus fitted was judged by examining how well these described the observed dwell-time distributions, open-shut correlation, and single-channel P open dose-response curve. We found that gating efficacy increased as more glycine molecules bind to the channel, but maximum efficacy was reached when only three (of five) potential binding sites are occupied. Successive binding steps are not identical, implying that binding sites can interact while the channel is shut. These interactions can be interpreted in the light of the topology of the binding sites within a homopentamer.

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Section: Introductionmentioning

confidence: 99%

The Activation Mechanism of α1 Homomeric Glycine Receptors

Beato

Groot-Kormelink²,

Colquhoun³

et al. 2004

J. Neurosci.

103

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“…There are two classes of glycine receptor subunits: the ␣ subunits, of which there are four subtypes, and one ␤ subunit (Lynch, 2004). Most native GlyRs in adult animals consist of heteromeric ␣1␤ subunits, although homomeric ␣2 subunits are the predominant form found prenatally (Rajendra and Schofield, 1995). The glycine ␣, but not ␤, subunits can form homomeric receptors that express well in a variety of receptor expression systems.…”

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confidence: 99%

Single-Channel Analysis of Ethanol Enhancement of Glycine Receptor Function

Welsh

Goldstein

Mihic³

2009

J Pharmacol Exp Ther

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The glycine receptor (GlyR) is a ligand-gated ion channel and member of the nicotinic acetylcholine receptor superfamily. Acting as allosteric modulators of receptor function, drugs such as alcohol and volatile anesthetics enhance the function of GlyRs. The actions of these drugs at inhibitory receptors in the brain and spinal cord are thought to produce many of the physiological effects associated with their use. The actions of ethanol on the GlyR have been well studied on the macroscopic, whole cell level. We examined the effects of 3 M glycine Ϯ 50 or 200 mM ethanol on outside-out patches pulled from Xenopus laevis oocytes expressing wild-type ␣1 GlyR, to determine the effects of alcohol at the single-channel level. Alcohol enhanced GlyR function in a very specific manner. It had minimal effects on open and closed dwell times and likelihood. Instead, ethanol potentiated GlyR function almost exclusively by increasing burst durations and increasing the number of channel openings per burst, without affecting the percentage of open time within bursts. Kinetic modeling suggests that ethanol increases burst durations by decreasing the rate of glycine unbinding.

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“…Inherited mutations located in the regions flanking the M2 domain of the GlyR ␣1-subunit are associated with human startle disease (hyperekplexia) (5) and startle syndromes in other species (6). In humans, the startle mutations R271L/Q and K276E map to the M2-M3 linker domain (5,7).…”

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confidence: 99%

Role of Charged Residues in Coupling Ligand Binding and Channel Activation in the Extracellular Domain of the Glycine Receptor

Absalom

Lewis

Kaplan

et al. 2003

Journal of Biological Chemistry

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The glycine receptor is a member of the ligand-gated ion channel receptor superfamily that mediates fast synaptic transmission in the brainstem and spinal cord. Following ligand binding, the receptor undergoes a conformational change that is conveyed to the transmembrane regions of the receptor resulting in the opening of the channel pore. Using the acetylcholine-binding protein structure as a template, we modeled the extracellular domain of the glycine receptor ␣1-subunit and identified the location of charged residues within loops 2 and 7 (the conserved Cys-loop). These loops have been postulated to interact with the M2-M3 linker region between the transmembrane domains 2 and 3 as part of the receptor activation mechanism. Charged residues were substituted with cysteine, resulting in a shift in the concentration-response curves to the right in each case. Covalent modification with 2-(trimethylammonium) ethyl methanethiosulfonate was demonstrated only for K143C, which was more accessible in the open state than the closed state, and resulted in a shift in the EC 50 toward wild-type values. Charge reversal mutations (E53K, D57K, and D148K) also impaired channel activation, as inferred from increases in EC 50 values and the conversion of taurine from an agonist to an antagonist in E53K and D57K. Thus, each of the residues Glu-53, Asp-57, Lys-143, and Asp-148 are implicated in channel gating. However, the double reverse charge mutations E53K:K276E, D57K:K276E, and D148K:K276E did not restore glycine receptor function. These results indicate that loops 2 and 7 in the extracellular domain play an important role in the mechanism of activation of the glycine receptor although not by a direct electrostatic mechanism.Fast synaptic transmission in the central nervous system is mediated by members of the ligand-gated ion channel (LGIC) 1 receptor superfamily. The glycine receptor (GlyR) is a member of the nicotinic-like LGIC superfamily that includes the nicotinic acetylcholine (nAChR), serotonin type 3 (5-HT 3 R), and ␥-aminobutyric acid (GABA A R) receptors (1, 2). Each of these receptors are pentameric complexes arranged around a central ion conducting pore. Individual subunits share a similar membrane topology, with hydropathy analysis predicting a large extracellular domain at the N terminus and four putative transmembrane domains (M1-M4) (1). A key characteristic of these receptors is the integral ion channel that is opened following ligand binding. The extracellular domain contains the ligand binding site, which is spatially separate from the M2 domain that lines the ion channel pore of these receptors (3, 4). While there is an accumulated body of data on the structures involved in ligand binding (2) and the ion channel pore (2-4), relatively little is known about the structures that may link these two spatially separate domains to effect receptor activation.Inherited mutations located in the regions flanking the M2 domain of the GlyR ␣1-subunit are associated with human startle disease (hyperekplexia) (5) and start...

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Molecular mechanisms of inherited startle syndromes

Cited by 40 publications

References 0 publications

The Activation Mechanism of α1 Homomeric Glycine Receptors

The Activation Mechanism of α1 Homomeric Glycine Receptors

Single-Channel Analysis of Ethanol Enhancement of Glycine Receptor Function

Role of Charged Residues in Coupling Ligand Binding and Channel Activation in the Extracellular Domain of the Glycine Receptor

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