Investigating the mechanism by which gain-of-function mutations to the a1 glycine receptor cause hyperekplexia

Zhang, Yan, Bode, Anna, Nguyen, Bindi, Angelo Keramidas and Lynch, Joseph W. (2016) Investigating the mechanism by which gain-of-function mutations to the a1 glycine receptor cause hyperekplexia. Journal of Biological Chemistry, 291 29: 15332-15341. doi:10.1074/jbc.M116.728592

Author Zhang, Yan
Bode, Anna
Nguyen, Bindi
Angelo Keramidas
Lynch, Joseph W.
Title Investigating the mechanism by which gain-of-function mutations to the a1 glycine receptor cause hyperekplexia
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2016-07-15
Year available 2016
Sub-type Article (original research)
DOI 10.1074/jbc.M116.728592
Open Access Status Not Open Access
Volume 291
Issue 29
Start page 15332
End page 15341
Total pages 10
Place of publication Rockville, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2017
Language eng
Formatted abstract
Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the α1 and β glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-of-function GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-of-function mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates α1β glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype.
Keyword Hyperekplexia
Inhibitory postsynaptic currents (IPSCs)
Glycine receptor (GlyR)2 chloride channels
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
School of Biomedical Sciences Publications
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Created: Tue, 02 Aug 2016, 15:42:30 EST by Angelo Keramidas on behalf of Queensland Brain Institute