Differential blockade of voltage-sensitive calcium channels at the mouse neuromuscular junction by novel ω-conopeptides and ω-agatoxin-IVA

S. S. Bowersox, G. P. Miljanich, Y. Sugiura, C. Li, L. Nadasdi, B. B. Hoffman, J. Ramachandran, C. P. Ko

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

This investigation assessed the ability of a variety of calcium channel blocking peptides to block synaptic transmission in the isolated mouse phrenic nerve-hemidiaphragm. The synthetic version of the naturally occurring N-type voltage-sensitive calcium channel (VSCC) blocker ω-conopeptide MVIIA (SNX-111) had no effect on nerve-evoked muscle contractions. The non-N-, non- L-type VSCC blocker, ω-conopeptide MVIIC (SNX-230), blocked neuromuscular transmission completely, as did the selective P-type VSCC blocker, ω-Aga- IVA. Subsequent evaluation of other synthetic ω-conopeptides and analogs disclosed a significant positive correlation between the test compounds' affinities for high-affinity SNX-230 brain binding sites and their neuromuscular blocking potencies. Quantal analysis of transmitter release showed that SNX-230 abolished evoked endplate potentials completely, but had little effect on the amplitude and frequency of spontaneous miniature endplate potentials. Perineural focal recordings of presynaptic currents showed that SNX-230 did not block the neuronal action potential. These and other findings indicated that SNX-230 prevents transmitter release at the mouse neuromuscular junction by blocking calcium channels at presynaptic nerve endings. These calcium channels correspond pharmacologically to VSCCs associated with high-affinity binding sites in rat brain and are most probably either of the P- or Q-type.

Original languageEnglish (US)
Pages (from-to)248-256
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume273
Issue number1
StatePublished - Apr 24 1995

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Bowersox, S. S., Miljanich, G. P., Sugiura, Y., Li, C., Nadasdi, L., Hoffman, B. B., Ramachandran, J., & Ko, C. P. (1995). Differential blockade of voltage-sensitive calcium channels at the mouse neuromuscular junction by novel ω-conopeptides and ω-agatoxin-IVA. Journal of Pharmacology and Experimental Therapeutics, 273(1), 248-256.