NEUROANATOMICAL DISTRIBUTION OF RECEPTORS FOR A NOVEL VOLTAGE-SENSITIVE CALCIUM-CHANNEL ANTAGONIST, SNX-230 (OMEGA-CONOPEPTIDE-MVIIC)

Neuronal voltage-sensitive calcium channels (VSCCs) are a diverse fami ly of proteins that regulate entry of Ca2+ into neurons. Selective ant agonists of VSCCs have proven to be powerful pharmacological tools for identifying and characterizing these channels. A new VSCC antagonist, SNX-230 (also known as omega-conopeptide MVIIC), binds with high affi nity to receptors in rat brain and blocks one or more high-threshold V SCCs that are neither L- nor N-type. We have defined the neuroanatomic al distribution of the high-affinity non-L, non-N VSCC receptors for S NX-230 using [I-125]SNX-230 bound to rat brain sections and compared i t with that of [(125)IISNX-111, a reversible blocker of N-type VSCCs. Highest densities of binding for both ligands were seen in areas rich in synaptic connections, such as the oriens, radiatum and molecular la yers of the hippocampus. In general, the density of [I-125]SNX-230-bin ding was higher in cerebellum compared with that in forebrain. In cont rast, this general distribution of density was reversed for [I-125]SNX -111. In the glomeruli of the olfactory bulb, binding of [I-125]SNX-23 0 was undetectable compared with the high density of [I-125]SNX-111-bi nding. Differential localization of the two ligands was also seen in c ervical spinal cord. The clearly different localization of I-125]SNX-2 30 compared with that of [I-125]SNX-111 in the olfactory bulb and spin al cord suggested that the binding sites for [I-125]SNX-230 in other b rain regions, while co-localized macroscopically, are also distinct fr om those for [I-125]SNX-113. This was confirmed when addition of satur ating concentrations of SNX-111 did not affect the distribution patter n of [I-125]SNX-230-binding. These observations demonstrate that the h igh-affinity [I-125]SNX-230 receptors in the brain and those of the N- type VSCCs are distinct molecular entities. Thus, SNX-230 (omega-MVIIC ) offers a useful ligand for investigating the distribution and functi ons of non-L-, non-N-type VSCCs in the brain.