title: Metabotropic glutamate receptor modulation of voltage-gated Ca2+ channels involves multiple receptor subtypes in cortical neurons.
abstract: Metabotropic glutamate receptor (mGluR) modulation of voltage-gated Ca2+ channels was examined in isolated deep layer frontoparietal cortical neurons under conditions designed to isolate calcium-independent modulatory pathways. Trans-1-aminocyclopentane-1,3-dicarboxylate (t-ACPD), a nonspecific mGluR agonist, produced rapid and reversible inhibition of Ca2+ channels. This effect was mimicked by agonists for group I and group II, but not group III, mGluRs. Effects of group I and II agonists often were observed in the same neurons, but separate subgroups of neurons were unresponsive to the group I agonist quisqualate or the group II agonist 2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV). Inhibition by quisqualate and DCG-IV was nonocclusive in neurons responding to both agonists. These agonists thus appear to act on different mGluRs. The mGluR antagonist alpha-methyl-4-carboxylphenylglycine attenuated inhibition by t-ACPD, quisqualate, and DCG-IV. Inhibition by quisqualate and DCG-IV was voltage-dependent. Although the effects of both agonists were greatly reduced by N-ethylmaleimide (NEM), inhibition by DCG-IV was more sensitive to NEM than inhibition by quisqualate. t-ACPD-induced inhibition was reduced by omega-conotoxin GVIA (omega-CgTx) and omega-agatoxin IVA (omega-AgTx) but was affected little by nifedipine. Inhibition by DCG-IV and quisqualate also was reduced by omega-CgTx. We conclude that multiple mGluR subtypes inhibit Ca2+ channels in cortical neurons and that N- and possibly P-type channels are inhibited. Modulation is via a rapid-onset, voltage-dependent mechanism that likely involves a pertussis toxin (PTX)-sensitive G-protein. Type I mGluRs may work via additional PTX-insensitive pathways.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
authors.forename: S
authors.initials: S
authors.lastname: Choi
authors.forename: D M
authors.initials: DM
authors.lastname: Lovinger
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004594:Electrophysiology; D005033:Ethylmaleimide / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D015640:Ion Channel Gating / Q000502:physiology; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure*; D009498:Neurotoxins / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013111:Spider Venoms / Q000494:pharmacology; D020867:omega-Agatoxin IVA; D020866:omega-Conotoxin GVIA
chemical_list: D001565:Benzoates; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003521:Cyclopropanes; D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D010455:Peptides; D018094:Receptors, Metabotropic Glutamate; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C079694:alpha-methyl-4-carboxyphenylglycine; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D016318:Quisqualic Acid; D020866:omega-Conotoxin GVIA; D009543:Nifedipine; D005033:Ethylmaleimide; D005998:Glycine