CALCIUM-CHANNEL ANTAGONIST PEPTIDES DEFINE SEVERAL COMPONENTS OF TRANSMITTER RELEASE IN THE HIPPOCAMPUS

The use of subtype-selective voltage-sensitive calcium channel (VSCC) antagonists has established that neurotransmitter release in mammalian brain is mediated by N-like and P-like VSCCs, and that other subtypes also contribute significantly. To determine the roles presynaptic VSC Cs play in nervous system function and to evaluate the therapeutic pot ential of their selective inhibition, it is necessary to define furthe r the contributions of VSCC subtypes to neurotransmitter release. The novel conopeptide, SNX-230 (omega-conopeptide MVIIC), has revealed a n ew VSCC subtype, the Q-type, in cerebellar granule cells. We have comp ared the effects of SNX-230 on release of tritiated D-aspartate ([H-3] D-Asp; a non-metabolizable analog of glutamate), gamma-aminobutyric ac id ([H-3]GABA), and norepinephrine ([H-3]NE) from rat hippocampal slic es to those of the N-type VSCC blocker, SNX-111 (omega-conopeptide MVI IA), and the P-type blocker, omega-agatoxin-IVA (AgaIVA). SNX-230 bloc ks both [H-3]D-Asp and [H-3]GABA release completely, whereas AgaIVA bl ocks them potently but partially and SNX-111 has no effect. These resu lts suggest that glutamate and GABA release are mediated by two VSCC s ubtypes, a P-type and another, perhaps Q-like. SNX-111 blocks [H-3]NE release potently but partially, while SNX-230 blockade is complete, co nsisting of one very potent phase and one less potent phase. AgaIVA al so blocks [H-3]NE release potently but partially. These results sugges t that at least two VSCC subtypes, an N-type and a novel non-N-type, m ediate NE release. Pair-wise combinations of the three ligands indicat e that at least three pharmacologically distinct components comprise [ H-3]NE release in the hippocampus.