{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:43:12Z","timestamp":1790433792261,"version":"4.1.0"},"reference-count":58,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T00:00:00Z","timestamp":1462838400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Hyperekplexia or startle disease is a serious neurological condition affecting newborn children and usually involves dysfunctional glycinergic neurotransmission.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Glycine receptors (GlyRs) are major mediators of inhibition in the spinal cord and brainstem.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>A missense mutation, replacing asparagine (N) with lysine (K), at position 46 in the GlyR \u03b11 subunit induced hyperekplexia following a reduction in the potency of the transmitter glycine; this resulted from a rapid deactivation of the agonist current at mutant GlyRs.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>These effects of N46K were rescued by mutating a juxtaposed residue, N61 on binding Loop D, suggesting these two asparagines may interact.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Asparagine 46 is considered to be important for the structural stability of the subunit interface and glycine binding site, and its mutation represents a new mechanism by which GlyR dysfunction induces startle disease.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Dysfunctional glycinergic inhibitory transmission underlies the debilitating neurological condition, hyperekplexia, which is characterised by exaggerated startle reflexes, muscle hypertonia and apnoea. Here we investigated the N46K missense mutation in the GlyR \u03b11 subunit gene found in the ethylnitrosourea (ENU) murine mutant,<jats:italic>Nmf11<\/jats:italic>, which causes reduced body size, evoked tremor, seizures, muscle stiffness, and morbidity by postnatal day 21. Introducing the N46K mutation into recombinant GlyR \u03b11 homomeric receptors, expressed in HEK cells, reduced the potencies of glycine, \u03b2\u2010alanine and taurine by 9\u2010, 6\u2010 and 3\u2010fold respectively, and that of the competitive antagonist strychnine by 15\u2010fold. Replacing N46 with hydrophobic, charged or polar residues revealed that the amide moiety of asparagine was crucial for GlyR activation. Co\u2010mutating N61, located on a neighbouring \u03b2 loop to N46, rescued the wild\u2010type phenotype depending on the amino acid charge. Single\u2010channel recording identified that burst length for the N46K mutant was reduced and fast agonist application revealed faster glycine deactivation times for the N46K mutant compared with the WT receptor. Overall, these data are consistent with N46 ensuring correct alignment of the \u03b11 subunit interface by interaction with juxtaposed residues to preserve the structural integrity of the glycine binding site. This represents a new mechanism by which GlyR dysfunction induces startle disease.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp272122","type":"journal-article","created":{"date-parts":[[2016,3,30]],"date-time":"2016-03-30T23:21:28Z","timestamp":1459380088000},"page":"3589-3607","source":"Crossref","is-referenced-by-count":11,"title":["Murine startle mutant<i>Nmf11<\/i>affects the structural stability of the glycine receptor and increases deactivation"],"prefix":"10.1113","volume":"594","author":[{"given":"Megan E.","family":"Wilkins","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology University College London Gower Street London WC1E 6BT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Caley","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology University College London Gower Street London WC1E 6BT 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