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Function of hyperekplexia-causing ?1R271Q/L glycine receptors is restored by shifting the affected residue out of the allosteric signalling pathway.

ABSTRACT: BACKGROUND AND PURPOSE Glycine receptor ?1 subunit R271Q and R271L (?1R271Q/L) mutations cause the neuromotor disorder, hereditary hyperekplexia. Studies suggest that the 271 residue is located within the allosteric signalling pathway linking the agonist binding site to the channel gate. The present study aimed to investigate a possible mechanism for restoring the function of the ?1R271Q/L glycine receptor. EXPERIMENTAL APPROACH A 12-amino-acid segment incorporating the 271 residue on the glycine receptor ?1271Q/L subunit was replaced by the homologous segment from the glycine receptor ? subunit (?1(Ch) 271Q/L). The function of the ?1(Ch) 271Q/L glycine receptor was examined by whole-cell patch-clamp recording and voltage-clamp fluorometry techniques. KEY RESULTS The function of the ?1(Ch) 271Q/L glycine receptor was restored to the level of the wild-type (WT) ?1 glycine receptor. Moreover, in the ?1(Ch) glycine receptor, in contrast to the ?1 glycine receptor, the channel function was not sensitive to various substitutions of the 271 residue, and the conformational change in the vicinity of the 271 residue was uncoupled from the channel gating. CONCLUSIONS AND IMPLICATIONS The 271 residue is shifted out of the allosteric signalling pathway in the ?1(Ch) glycine receptor. We propose that this mechanism provides a novel drug design strategy not only for glycine receptor ?1R271Q/L-caused hereditary hyperekplexia, but also for any pathological condition that is caused by missense mutation- or covalent modification-induced disorders involving residues in allosteric signalling pathways. Such a strategy makes it possible to design an ideal drug, which only corrects the function of the mutant or modified protein without affecting the WT or naive protein.

SUBMITTER: Shan Q

PROVIDER: S-EPMC3413849 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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Function of hyperekplexia-causing α1R271Q/L glycine receptors is restored by shifting the affected residue out of the allosteric signalling pathway.

Shan Qiang Q Han Lu L Lynch Joseph W JW

British journal of pharmacology 20120401 7

BACKGROUND AND PURPOSE Glycine receptor α1 subunit R271Q and R271L (α1R271Q/L) mutations cause the neuromotor disorder, hereditary hyperekplexia. Studies suggest that the 271 residue is located within the allosteric signalling pathway linking the agonist binding site to the channel gate. The present study aimed to investigate a possible mechanism for restoring the function of the α1R271Q/L glycine receptor. EXPERIMENTAL APPROACH A 12-amino-acid segment incorporating the 271 residue on the glycin ...[more]

PMID: 21955162

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Project description:Glycine receptors are ligand-gated ion channels that mediate synaptic inhibition throughout the mammalian spinal cord, brainstem, and higher brain regions. They have recently emerged as promising targets for novel pain therapies due to their ability to produce antinociception by inhibiting nociceptive signals within the dorsal horn of the spinal cord. This has greatly enhanced the interest in developing positive allosteric modulators of glycine receptors. Several pharmaceutical companies and research facilities have attempted to identify new therapeutic leads by conducting large-scale screens of compound libraries, screening new derivatives from natural sources, or synthesizing novel compounds that mimic endogenous compounds with antinociceptive activity. Advances in structural techniques have also led to the publication of multiple high-resolution structures of the receptor, highlighting novel allosteric binding sites and providing additional information for previously identified binding sites. This has greatly enhanced our understanding of the functional properties of glycine receptors and expanded the structure activity relationships of novel pharmacophores. Despite this, glycine receptors are yet to be used as drug targets due to the difficulties in obtaining potent, selective modulators with favorable pharmacokinetic profiles that are devoid of side effects. This review presents a summary of the structural basis for how current compounds cause positive allosteric modulation of glycine receptors and discusses their therapeutic potential as analgesics. SIGNIFICANCE STATEMENT: Chronic pain is a major cause of disability, and in Western societies, this will only increase as the population ages. Despite the high level of prevalence and enormous socioeconomic burden incurred, treatment of chronic pain remains limited as it is often refractory to current analgesics, such as opioids. The National Institute for Drug Abuse has set finding effective, safe, nonaddictive strategies to manage chronic pain as their top priority. Positive allosteric modulators of glycine receptors may provide a therapeutic option.

Dataset Information

Function of hyperekplexia-causing ?1R271Q/L glycine receptors is restored by shifting the affected residue out of the allosteric signalling pathway.

Publications

Function of hyperekplexia-causing α1R271Q/L glycine receptors is restored by shifting the affected residue out of the allosteric signalling pathway.

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