mu O-conotoxin MrVIA inhibits mammalian sodium channels, but not through site I

1. A 31-amino-acid peptide from the venom of the snail-hunting species Conus marmoreus, mu O-conotoxin MrVIA, inhibits mammalian voltage-gated sodium channels through a novel mechanism distinct from saxitoxin, tetrodotoxin, or mu-conotoxin. 2. mu O-Conotoxin MrVIA blocks rat brain type II sodium channels expressed in Xenopus oocytes (IC50 similar to 200 nhl, Hill coefficient similar to 1.6 +/- 0.2, mean +/- SE). Channel activation/inactivation kinetics and current-voltage relationships were unperturbed. 3. mu O-Conotoxin MrVIA does not cause phasic or use-dependent inhibition of sodium currents measured in Xenopus oocytes expressing rat brain type II sodium channels, but shifts the steady-state availability of these sodium channels to more hyperpolarized potentials. 4. mu O-Conotoxin MrVIA inhibited rapidly inactivating sodium channel conductance in rat hippocampal cells in culture. The inhibition was rapidly reversible. 5. mu O-Conotoxin MrVIA does not displace specific [H-3]saxitoxin binding to either rat brain or Electrophorus electric organ sites, indicating inhibitory effects mediated through a binding site distinct from site I.