Matches in SemOpenAlex for { <https://semopenalex.org/work/W2407862355> ?p ?o ?g. }
- W2407862355 endingPage "15341" @default.
- W2407862355 startingPage "15332" @default.
- W2407862355 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. 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." @default.
- W2407862355 created "2016-06-24" @default.
- W2407862355 creator A5013604984 @default.
- W2407862355 creator A5027657793 @default.
- W2407862355 creator A5028546496 @default.
- W2407862355 creator A5042940621 @default.
- W2407862355 creator A5067920816 @default.
- W2407862355 date "2016-07-01" @default.
- W2407862355 modified "2023-10-05" @default.
- W2407862355 title "Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia" @default.
- W2407862355 cites W1879293587 @default.
- W2407862355 cites W1963740158 @default.
- W2407862355 cites W1965996413 @default.
- W2407862355 cites W1967639688 @default.
- W2407862355 cites W1974993251 @default.
- W2407862355 cites W1978674163 @default.
- W2407862355 cites W1980983414 @default.
- W2407862355 cites W1981111905 @default.
- W2407862355 cites W1981857440 @default.
- W2407862355 cites W1988936493 @default.
- W2407862355 cites W1990816409 @default.
- W2407862355 cites W1995290394 @default.
- W2407862355 cites W1996517727 @default.
- W2407862355 cites W1996731621 @default.
- W2407862355 cites W1997505926 @default.
- W2407862355 cites W2016676279 @default.
- W2407862355 cites W2021842829 @default.
- W2407862355 cites W2031876182 @default.
- W2407862355 cites W2033843602 @default.
- W2407862355 cites W2038436836 @default.
- W2407862355 cites W2066452885 @default.
- W2407862355 cites W2068001362 @default.
- W2407862355 cites W2073018978 @default.
- W2407862355 cites W2076793364 @default.
- W2407862355 cites W2079066138 @default.
- W2407862355 cites W2081392226 @default.
- W2407862355 cites W2091997673 @default.
- W2407862355 cites W2094183469 @default.
- W2407862355 cites W2098260634 @default.
- W2407862355 cites W2102431257 @default.
- W2407862355 cites W2104004306 @default.
- W2407862355 cites W2108554908 @default.
- W2407862355 cites W2109655332 @default.
- W2407862355 cites W2110107835 @default.
- W2407862355 cites W2117449859 @default.
- W2407862355 cites W2121372715 @default.
- W2407862355 cites W2126111994 @default.
- W2407862355 cites W2127772252 @default.
- W2407862355 cites W2130433492 @default.
- W2407862355 cites W2135870535 @default.
- W2407862355 cites W2136456229 @default.
- W2407862355 cites W2142932014 @default.
- W2407862355 cites W2161121393 @default.
- W2407862355 cites W2169652081 @default.
- W2407862355 cites W2219548386 @default.
- W2407862355 cites W2238263941 @default.
- W2407862355 cites W2289571853 @default.
- W2407862355 cites W4211205348 @default.
- W2407862355 cites W2015326690 @default.
- W2407862355 doi "https://doi.org/10.1074/jbc.m116.728592" @default.
- W2407862355 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4946944" @default.
- W2407862355 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27226610" @default.
- W2407862355 hasPublicationYear "2016" @default.
- W2407862355 type Work @default.
- W2407862355 sameAs 2407862355 @default.
- W2407862355 citedByCount "15" @default.
- W2407862355 countsByYear W24078623552016 @default.
- W2407862355 countsByYear W24078623552017 @default.
- W2407862355 countsByYear W24078623552018 @default.
- W2407862355 countsByYear W24078623552019 @default.
- W2407862355 countsByYear W24078623552020 @default.
- W2407862355 countsByYear W24078623552021 @default.
- W2407862355 countsByYear W24078623552022 @default.
- W2407862355 crossrefType "journal-article" @default.
- W2407862355 hasAuthorship W2407862355A5013604984 @default.
- W2407862355 hasAuthorship W2407862355A5027657793 @default.
- W2407862355 hasAuthorship W2407862355A5028546496 @default.
- W2407862355 hasAuthorship W2407862355A5042940621 @default.
- W2407862355 hasAuthorship W2407862355A5067920816 @default.
- W2407862355 hasBestOaLocation W24078623551 @default.
- W2407862355 hasConcept C104317684 @default.
- W2407862355 hasConcept C126322002 @default.
- W2407862355 hasConcept C168258287 @default.
- W2407862355 hasConcept C169760540 @default.
- W2407862355 hasConcept C170493617 @default.
- W2407862355 hasConcept C17077164 @default.
- W2407862355 hasConcept C185592680 @default.
- W2407862355 hasConcept C200170125 @default.
- W2407862355 hasConcept C2777756961 @default.
- W2407862355 hasConcept C2779177108 @default.
- W2407862355 hasConcept C35599011 @default.
- W2407862355 hasConcept C501734568 @default.
- W2407862355 hasConcept C515207424 @default.
- W2407862355 hasConcept C54355233 @default.
- W2407862355 hasConcept C71924100 @default.
- W2407862355 hasConcept C86803240 @default.
- W2407862355 hasConcept C95444343 @default.
- W2407862355 hasConceptScore W2407862355C104317684 @default.