2. Academic Validation
  3. Complete reversal of Lambert-Eaton myasthenic syndrome synaptic impairment by the combined use of a K+ channel blocker and a Ca2+ channel agonist

Complete reversal of Lambert-Eaton myasthenic syndrome synaptic impairment by the combined use of a K+ channel blocker and a Ca2+ channel agonist

  • J Physiol. 2014 Aug 15;592(16):3687-96. doi: 10.1113/jphysiol.2014.276493.
Tyler B Tarr 1,  David Lacomis 2,  Stephen W Reddel 3,  Mary Liang 4,  Guillermo Valdomir 4,  Michael Frasso 4,  Peter Wipf 4,  Stephen D Meriney 5
Affiliations

Affiliations

  • 1 Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA.
  • 2 Division of Neuromuscular Diseases, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Department of Clinical Neurology, Concord Hospital, Sydney, NSW, Australia.
  • 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA meriney@pitt.edu.
PMID: 25015919 DOI: 10.1113/jphysiol.2014.276493
Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder in which a significant fraction of the presynaptic P/Q-type CA(2+) 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-diaminopyridine (3,4-DAP)] that does not completely reverse symptoms and can have dose-limiting side-effects. We previously reported the development of a novel CA(2+) channel agonist, GV-58, as a possible alternative treatment strategy for LEMS. In this study, we tested the hypothesis that the combination of GV-58 and 3,4-DAP will elicit a supra-additive increase in neurotransmitter release at LEMS model NMJs. First, we tested GV-58 in a cell survival assay to assess potential effects on cyclin-dependent kinases (Cdks) and showed that GV-58 did not affect cell survival at the relevant concentrations for CA(2+) channel effects. Then, we examined the voltage dependence of GV-58 effects on CA(2+) channels using patch clamp techniques; this showed the effects of GV-58 to be dependent upon CA(2+) channel opening. Based on this mechanism, we predicted an interaction between 3,4-DAP and GV-58. We tested this hypothesis using a mouse passive transfer model of LEMS. Using intracellular electrophysiological ex vivo recordings, we demonstrated that a combined application of 3,4-DAP plus GV-58 had a supra-additive 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-DAP and GV-58 represents a promising treatment option for LEMS and potentially for Other disorders of the NMJ.

Figures
Products