Conus venoms contain a remarkable diversity of pharmacologically active small peptides. Their targets are ion channels and receptors in the neuromuscular system. The venom of Conus geographus contains high-affinity peptides that act on voltage-sensitive calcium channels, sodium channels, N-methyl-D-aspartate (NMDA) receptors, acetylcholine receptors, and vasopressin receptors; many more peptides with still uncharacterized receptor targets are present in this venom. It now seems that the Conus species (approximately 500 in number) will each use a distinctive assortment of peptides and that the pharmacological diversity in Conus venoms may be ultimately comparable to that of plant alkaloids or secondary metabolites of microorganisms. The cone snails may generate this diverse spectrum of venom peptides by a "fold-lock-cut" synthetic pathway. These peptides are specific enough to discriminate effectively between closely related receptor subtypes and can be used for structure-function correlations.

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The heterocyclic compound kainic acid (KA) is a potent excitant when applied to mammalian neurones. Lesions caused by injections of KA into the rat striatum and hippocampus cause similar patterns of damage to those seen in Huntington's chorea and status epilepticus, respectively. Although it was originally thought to be a glutamate agonist, it is now clear that KA does not act on the majority of the receptors for glutamate, and in fact seems to act on a class of receptors which are distinct from those which mediate responses to other excitatory amino acids. The potent and selective neurotoxic effects of this compound may be mediated by these same receptors. At present, the relative distribution of junctional and extrajunctional (non-synaptic) receptors is unknown and resolution of this issue would provide important insights into the action of KA on the central nervous system (CNS). We show here that KA binding sites are greatly enriched in isolated synaptic junctions from rat brain and, using an in vitro autoradiographic technique, we have found that these binding sites are concentrated specifically in terminal fields where KA acts as a potent neurotoxin.

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The effects of Cl-and Ca2+ on the specific binding of L-glutamate and L-aspartate to synaptic plasma membranes (SPMs) were examined. At a concentration of 2.5 mM, CaClz augmented Lglutamate binding 3.34-fold and modified its pharmacological specificity, whereas L-aspartate binding was unaffected. Kinetic analyses of the inhibition of L-glutamate binding by the a-amino-w-phosphonic acid derivatives of propionic (APP), butyric (APB), and valeric (APV) acids demonstrated that, in the presence of CaC12, these homologues competed for the same L-glutamate binding site with Ki values of 16 PM (APB), 39 PM (APV), and >l mM (APP); the L isomer of APB was 15-fold more potent than the D form (Ki values, 5 and 75 PM, respectively). Hill plots indicated an absence of cooperative interactions. These Ki values are in close agreement with those determined electrophysiologically for the antagonism of perforant path-granule cell synaptic transmission in the rat dentate gyrus in vitro (Koerner, J. F., and C. W. Cotman (1981) Brain Res. 216: 192-198). In the presence of CaCl2, approximately 80% of the L-glutamate binding sites were sensitive to inhibition by the phosphonic acid derivatives, and experiments with APB indicated that the insensitive sites could be equated with the CaClz-independent sites. Investigations with Cl-and Ca2+ separately and in combination suggested that Cl-is necessary to unmask the APB-sensitive sites and that Ca2+ is required to reveal the full extent of this response. Further studies showed that the Cll/Ca"+-dependent APB-sensitive L-glutamate binding sites are enriched in SPMs (relative to total particulate and crude mitochondrial fractions) and that these sites are sensitive to inhibition by a number of compounds with agonist or antagonist properties at excitatory amino acid receptor sites. These data indicate that Cl-and Ca2+ unmask a pharmacologically distinct population of L-glutamate binding sites which are of physiological significance for acidic amino acid-mediated synaptic transmission in the brain. Electrophysiologicalstudies have demonstrated the presence of multiple excitatory amino acid receptor types on neurons of the mammalian central nervous system (CNS).4 Examination of a large number of excitants and ' We would like to thank Professors