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 language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1995|
ASJC Scopus subject areas
- Molecular Medicine