DIFFERENTIAL BLOCKADE OF VOLTAGE-SENSITIVE CALCIUM CHANNELS AT THE MOUSE NEUROMUSCULAR-JUNCTION BY NOVEL OMEGA-CONOPEPTIDES AND OMEGA-AGATOXIN-IVA

This investigation assessed the ability of a variety of calcium channe l blocking peptides to block synaptic transmission in the isolated mou se phrenic nerve-hemidiaphragm. The synthetic version of the naturally occurring N-type voltage-sensitive calcium channel (VSCC) blocker ome ga-conopeptide MVIIA (SNX-111) had no effect on nerve-evoked muscle co ntractions. The non-N-, non-L-type VSCC blocker, omega-conopeptide MVI IC (SNX-230), blocked neuromuscular transmission completely, as did th e selective P-type VSCC blocker, omega-Aga-IVA. Subsequent evaluation of other synthetic omega-conopeptides and analogs disclosed a signific ant positive correlation between the test compounds' affinities for hi gh-affinity SNX-230 brain binding sites and their neuromuscular blocki ng potencies. Quantal analysis of transmitter release showed that SNX- 230 abolished evoked endplate potentials completely, but had little ef fect 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 o ther findings indicated that SNX-230 prevents transmitter release at t he mouse neuromuscular junction by blocking calcium channels at presyn aptic nerve endings. These calcium channels correspond pharmacological ly to VSCCs associated with high-affinity binding sites in rat brain a nd are most probably either of the P- or Q-type.