Voltage-sensitive Ca2+ channels that control neurotransmitter release are blocked by omega-conotoxin (omega-CgTx) GVIA from the marine snail Conus geographus, the most widely used inhibitor of neurotransmitter release. However, many mammalian synapses are omega-CgTx-GVIA insensitive. We describe a new Conus peptide, omega-CgTx-MVIIC, that is an effective inhibitor of omega-CgTx-GVIA-resistant synaptic transmission. Ca2+ channel targets that are inhibited by omega-CgTx-MVIIC but not by omega-CgTx-GVIA include those mediating depolarization-induced 45Ca2+ uptake in rat synaptosome preparations, “P” currents in cerebellar Purkinje cells, and a subset of omega-CgTx-GVIA-resistant currents in CA1 hippocampal pyramidal cells. The characterization of omega-CgTx-MVIIC by a combination of molecular genetics and chemical synthesis defines a general approach for obtaining ligands with novel receptor subtype specificity from Conus.

Hillyard, D. R., et al. (1992) A new Conus peptide ligand for mammalian presynaptic Ca2+ channels, Neuron. PMID: 1352986

High-threshold voltage-sensitive calcium channels of the N-type, L-type, and P-type have been distinguished in the mammalian CNS predominantly on the basis of their sensitivity to selective antagonists. Matching them with genes identified by molecular cloning is an ongoing undertaking. Whereas L-type channels are characterized by their sensitivity to dihydropyridines and P-type channels by sensitivity to the funnel-web spider toxin AgaIVA, the N-type channel has been shown to be recognized by the omega-conopeptides GVIA and MVIIA. Recently, two new members of the family of omega-conopeptides–MVIIC from the marine snail Conus magus and SVIB from Conus striatus–have been described. Binding and electrophysiological data suggest that these two peptides, in addition to interacting with N-type calcium channels, interact with a widely distributed receptor in neuronal membranes that is distinct from N-type channels. In this report we demonstrate through biochemical and pharmacological differentiation at individual receptor polypeptide resolution, by affinity cross-linking, SDS-PAGE, and autoradiography, that SNX-230 (synthetic MVIIC) binds with high affinity to a calcium channel alpha 1 subunit distinct from the high-affinity alpha 1 target of SNX-111 (synthetic MVIIA). SNX-183 (synthetic SVIB) interacts with both alpha 1 subunits with lower affinity. Whereas the alpha 1 subunit recognized with high affinity by MVIIA corresponds to the N-type channel, the other represents a novel calcium channel distinct from N-, L-, and perhaps P-type channels.

Woppmann A, (1994) Calcium channel subtypes in rat brain: biochemical characterization of the high-affinity receptors for omega-conopeptides SNX-230 (synthetic MVIIC), SNX-183 (SVIB), and SNX-111 (MVIIA), Mol Cell Neurosci. PMID: 7804605

We have investigated the effects of omega-CmTX MVIIC on the recombinant alpha 1B-mediated calcium channel expressed in HEK 293 cells and on the predominantly N-type calcium channel in chick synaptosomes. omega-CmTX MVIIC potently and reversibly inhibited the calcium current through alpha 1B-mediated calcium channels and inhibited KCl-evoked increases in [Ca2+]i in chick synaptosomes in a concentration-dependent manner.

Grantham CJ, (1994) Omega-conotoxin MVIIC reve rsibly inhibits a human N-type calcium channel and calcium influx into chick synaptosomes, Neuropharmacology. PMID: 8035912