title: Physiological activation of presynaptic metabotropic glutamate receptors increases intracellular calcium and glutamate release.
abstract: Activation of metabotropic glutamate receptors (mGluRs) has diverse effects on the functioning of vertebrate synapses. The cellular mechanisms that underlie these changes, however, are largely unknown. The role of presynaptic mGluRs in modulating Ca(2+) dynamics and regulating neurotransmitter release was investigated at the vestibulospinal-reticulospinal (VS-RS) synapse in the lamprey brain stem. Application of the specific Group I mGluRs antagonist 7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) reduced the amplitude of consecutive high-frequency evoked excitatory postsynaptic currents (EPSCs). A series of experiments using techniques of electrophysiology and calcium imaging were carried out to determine the cellular mechanisms by which this phenomenon occurs. Concentration-dependent increases in the pre- and postsynaptic [Ca(2+)](i) were seen with the application of mGluR agonists. Similarly, high-frequency stimulation of axons caused a Group I mGluR-dependent enhancement in presynaptic Ca(2+) transients. Application of mGluR agonist caused a depolarization of the presynaptic elements, while thapsigargin decreased the high-frequency stimulus- and agonist-induced rises in [Ca(2+)](i). These data suggest that both membrane depolarization and the release of Ca(2+) from intracellular stores potentially play a role in mGluR-induced Ca(2+) signaling. To determine the effect of this modulation of Ca(2+) dynamics on spontaneous glutamate release, miniature EPSCs were recorded from postsynaptic reticulospinal neurons. A potent Group I mGluR agonist, (S)-homoquisqualic acid, caused a large increase in the frequency of events. These results demonstrate the presence of presynaptic Group I mGluRs at the VS-RS synapse. Activation of these receptors leads to a rise in [Ca(2+)](i) and enhances the spontaneous and evoked release of glutamate. Taken together, these studies highlight the importance of synaptic activation of these facilitatory autoreceptors in both short-term plasticity and synaptic transmission.
authors.affiliation: Department of Physiology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Schwartz
authors.forename: S
authors.initials: S
authors.lastname: Alford
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000737:chemistry / Q000502:physiology; D001933:Brain Stem / Q000166:cytology / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D003712:Dendrites / Q000737:chemistry / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005470:Fluorometry; D019204:GTP-Binding Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D018684:Glycine Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007798:Lampreys; D007814:Larva; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000737:chemistry* / Q000502:physiology; D016318:Quisqualic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013331:Strychnine / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D002867:Chromones; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C111256:homoquisqualic acid; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D018698:Glutamic Acid; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016318:Quisqualic Acid; D019204:GTP-Binding Proteins; D013331:Strychnine; D002118:Calcium