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 Citations (Scopus)

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 - 1995

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Agatoxins
Neuromuscular Junction
Calcium Channels
Calcium Channel Blockers
Binding Sites
Phrenic Nerve
Presynaptic Terminals
Brain
Muscle Contraction
Evoked Potentials
Synaptic Transmission
Action Potentials
omega-conotoxin-MVIIC
Peptides

ASJC Scopus subject areas

  • Pharmacology

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Differential blockade of voltage-sensitive calcium channels at the mouse neuromuscular junction by novel ω-conopeptides and ω-agatoxin-IVA. / Bowersox, S. S.; Miljanich, G. P.; Sugiura, Y.; Li, C.; Nadasdi, L.; Hoffman, B. B.; Ramachandran, J.; Ko, C. P.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 273, No. 1, 1995, p. 248-256.

Research output: Contribution to journalArticle

Bowersox, SS, Miljanich, GP, Sugiura, Y, Li, C, Nadasdi, L, Hoffman, BB, Ramachandran, J & Ko, CP 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, vol. 273, no. 1, pp. 248-256.
Bowersox, S. S. ; Miljanich, G. P. ; Sugiura, Y. ; Li, C. ; Nadasdi, L. ; Hoffman, B. B. ; Ramachandran, J. ; Ko, C. P. / Differential blockade of voltage-sensitive calcium channels at the mouse neuromuscular junction by novel ω-conopeptides and ω-agatoxin-IVA. In: Journal of Pharmacology and Experimental Therapeutics. 1995 ; Vol. 273, No. 1. pp. 248-256.
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