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NEUROPHARMACOLOGY

Noncompetitive Metabotropic Glutamate₅ Receptor Antagonist (E)-2-Methyl-6-styryl-pyridine (SIB1893) Depresses Glutamate Release through Inhibition of Voltage-Dependent Ca²⁺ Entry in Rat Cerebrocortical Nerve Terminals (Synaptosomes)

Department of Pharmacology, University College London, London, United Kingdom (T.S.S.); and School of Medicine, Fu Jen Catholic University, Taipei Hsien, Taiwan (S.J.W.)

The effect of (E)-2-methyl-6-styryl-pyridine (SIB1893), a selective metabotropic glutamate (subtype 5) receptor (mGlu₅R) antagonist, on glutamate release from isolated nerve terminals (synaptosomes) was examined. SIB1893 caused a potent inhibition of the Ca²⁺-dependent release of glutamate evoked by 4-aminopyridine (4AP). That the implied mGlu₅R-mediated modulation was contingent on diacylglycerol stimulation of protein kinase C (PKC) was indicated by PKC activator phorbol dibutyrate and PKC inhibitor Ro 32-0432 (bisindolylmaleimide XI), respectively, superceding or suppressing the inhibitory effect of SIB1893. The inhibitory action of SIB1893 was not due to it decreasing synaptosomal excitability or directly interfering with the release process at some point subsequent to Ca²⁺ influx, because SIB1893 did not alter the 4AP-evoked depolarization of the synaptosomal plasma membrane potential or Ca²⁺ ionophore ionomycin-induced glutamate release. Rather, examination of the effect of SIB1893 on cytosolic [Ca²⁺] revealed that the diminution of glutamate release could be attributed to a reduction in voltage-dependent Ca²⁺ influx. Consistent with this, the SIB1893-mediated inhibition of glutamate release was completely prevented in synaptosomes pretreated with a combination of the N- and P/Q-type Ca²⁺ channel blockers, -conotoxin GVIA, and -agatoxin IVA. Together, these results suggest that noncompetitive antagonism of mGlu₅Rs using SIB1893 effects a decrease in PKC activation, which subsequently attenuates the Ca²⁺ entry through voltage-dependent N- and P/Q-type Ca²⁺ channels to cause a decrease in evoked glutamate release. These actions of SIB1893 and related agents may contribute to their neuroprotective effects in excitotoxic injury.

Address correspondence to: Dr. Talvinder S. Sihra, Department of Pharmacology, University College London, Gower St., London WC1E 6BT, UK. E-mail: t.sihra{at}ucl.ac.uk