{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T02:07:52Z","timestamp":1783044472247,"version":"3.54.6"},"reference-count":38,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2014,7,16]],"date-time":"2014-07-16T00:00:00Z","timestamp":1405468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Achievement Rewards for College Scientists (ARCS)"},{"name":"National Science Foundation","award":["0844604"],"award-info":[{"award-number":["0844604"]}]},{"name":"National Science Foundation","award":["1249546"],"award-info":[{"award-number":["1249546"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["GM067082"],"award-info":[{"award-number":["GM067082"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"crossref","award":["295271"],"award-info":[{"award-number":["295271"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Myasthenia Associations of Australia and the Beeren Foundation"},{"name":"University of Pittsburgh Central Research Development Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2014,8,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Lambert\u2013Eaton myasthenic syndrome (LEMS) is characterized by an autoimmune\u2010mediated attack on presynaptic P\/Q\u2010type Ca<jats:sup>2+<\/jats:sup> channels at the neuromuscular junction (NMJ).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The current common symptomatic treatment option is 3,4\u2010diaminopyridine (3,4\u2010DAP), a potassium channel blocker that widens the presynaptic action potential, causing an increase in the amount of neurotransmitter release. This approach, however, does not completely reverse symptoms and can have dose\u2010limiting side\u2010effects. Thus, there is a need for additional treatment options.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We show that GV\u201058, a Ca<jats:sup>2+<\/jats:sup> channel agonist developed from the cyclin\u2010dependent kinase inhibitor (<jats:italic>R<\/jats:italic>)\u2010roscovitine, does not significantly inhibit cell division at physiological levels of ATP.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We further show that GV\u201058 has a greater agonist effect when more Ca<jats:sup>2+<\/jats:sup> channels are open, and combining GV\u201058 and 3,4\u2010DAP elicits a supra\u2010additive effect that completely restores the magnitude of neurotransmitter release in LEMS model NMJs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results suggest that a combination of GV\u201058 and 3,4\u2010DAP is promising as a possible alternative treatment approach to LEMS and other neuromuscular diseases.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Lambert\u2013Eaton myasthenic syndrome (LEMS) is an autoimmune disorder in which a significant fraction of the presynaptic P\/Q\u2010type Ca<jats:sup>2+<\/jats:sup> channels critical to the triggering of neurotransmitter release at the neuromuscular junction (NMJ) are thought to be removed. There is no cure for LEMS, and the current most commonly used symptomatic treatment option is a potassium channel blocker [3,4\u2010diaminopyridine (3,4\u2010DAP)] that does not completely reverse symptoms and can have dose\u2010limiting side\u2010effects. We previously reported the development of a novel Ca<jats:sup>2+<\/jats:sup> channel agonist, GV\u201058, as a possible alternative treatment strategy for LEMS. In this study, we tested the hypothesis that the combination of GV\u201058 and 3,4\u2010DAP will elicit a supra\u2010additive increase in neurotransmitter release at LEMS model NMJs. First, we tested GV\u201058 in a cell survival assay to assess potential effects on cyclin\u2010dependent kinases (Cdks) and showed that GV\u201058 did not affect cell survival at the relevant concentrations for Ca<jats:sup>2+<\/jats:sup> channel effects. Then, we examined the voltage dependence of GV\u201058 effects on Ca<jats:sup>2+<\/jats:sup> channels using patch clamp techniques; this showed the effects of GV\u201058 to be dependent upon Ca<jats:sup>2+<\/jats:sup> channel opening. Based on this mechanism, we predicted an interaction between 3,4\u2010DAP and GV\u201058. We tested this hypothesis using a mouse passive transfer model of LEMS. Using intracellular electrophysiological <jats:italic>ex vivo<\/jats:italic> recordings, we demonstrated that a combined application of 3,4\u2010DAP plus GV\u201058 had a supra\u2010additive effect that completely reversed the deficit in neurotransmitter release magnitude at LEMS model NMJs. This reversal contrasts with the less significant improvement observed with either compound alone. Our data indicate that a combination of 3,4\u2010DAP and GV\u201058 represents a promising treatment option for LEMS and potentially for other disorders of the NMJ.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jphysiol.2014.276493","type":"journal-article","created":{"date-parts":[[2014,7,12]],"date-time":"2014-07-12T04:19:42Z","timestamp":1405138782000},"page":"3687-3696","source":"Crossref","is-referenced-by-count":30,"title":["Complete reversal of Lambert\u2013Eaton myasthenic syndrome synaptic impairment by the combined use of a K<sup>+<\/sup> channel blocker and a Ca<sup>2+<\/sup> channel agonist"],"prefix":"10.1113","volume":"592","author":[{"given":"Tyler B.","family":"Tarr","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Center for Neuroscience University of Pittsburgh  Pittsburgh PA USA"},{"name":"Center for the Neural Basis of Cognition University of Pittsburgh  Pittsburgh PA 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