METABOTROPIC GLUTAMATE-RECEPTOR MODULATION OF VOLTAGE-GATED CA2-NEURONS( CHANNELS INVOLVES MULTIPLE RECEPTOR SUBTYPES IN CORTICAL)

Metabotropic glutamate receptor (mGluR) modulation of voltage-gated Ca 2+ channels was examined in isolated deep layer frontoparietal cortica l neurons under conditions designed to isolate calcium-independent mod ulatory pathways. Trans-1-aminocyclopentane-1,3-dicarboxylate (t-ACPD) , a nonspecific mGluR agonist, produced rapid and reversible inhibitio n of Ca2+ channels. This effect was mimicked by agonists for group I a nd group II, but not group III, mGluRs. Effects of group I and II agon ists often were observed in the same neurons, but separate subgroups o f neurons were unresponsive to the group I agonist quisqualate or the group II agonist 2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV). Inhibi tion by quisqualate and DCG-IV was nonocclusive in neurons responding to both agonists. These agonists thus appear to act on different mGluR s. The mGluR antagonist alpha-methyl-4-carboxylphenylglycine attenuate d inhibition by t-ACPD, quisqualate, and DCG-IV. Inhibition by quisqua late and DCG-IV was voltage-dependent. Although the effects of both ag onists were greatly reduced by M-ethylmaleimide (NEM), inhibition by D CG-IV was more sensitive to NEM than inhibition by quisqualate. t-ACPD -induced inhibition was reduced by omega-conotoxin GVIA (omega-CgTx) a nd omega-agatoxin IVA (omega-AgTx) but was affected little by nifedipi ne. Inhibition by DCG-IV and quisqualate also was reduced by omega-CgT x. We conclude that multiple mGluR subtypes inhibit Ca2+ channels in c ortical neurons and that N- and possibly P-type channels are inhibited . Modulation is via a rapid-onset, voltage-dependent mechanism that li kely involves a pertussis toxin (PTX)-sensitive G-protein, Type I mGlu Rs may work via additional PTX-insensitive pathways.