title: Presynaptic G Protein-Coupled Receptors Differentially Modulate Spontaneous Glutamate Release in the Supraoptic Nucleus.
abstract: Spontaneous glutamate release in the supraoptic nucleus is modulated by a number of inhibitory G protein coupled receptors (GPCR), including GABAB , adenosine A1 and group III metabotropic glutamate receptors (mGluR). It remains unclear whether they have distinct roles or are redundant mechanisms that protect from hyperexcitation. To address this question, we facilitated spontaneous glutamate release using nifedipine or forskolin, which act in a protein kinase A (PKA)-independent and -dependent manner, respectively, and tested the effects of inhibitory GPCR agonists. We found that a GABAB receptor (GABAB R) agonist specifically inhibited forskolin-induced miniature excitatory postsynaptic currents (mEPSC), in contrast to an adenosine A1 receptor (A1R) agonist, which specifically inhibited nifedipine-induced mEPSCs. This suggests that GABAB Rs and A1 Rs modulate independent mechanisms activated by forskolin and nifedipine, respectively. However, the inhibitory effects of GABAB R and A1 R agonists on basal mEPSCs occluded each other, suggesting that these receptors also have an overlapping role. Group III mGluRs appear to have a greater control over glutamate release because agonists to these receptors inhibited both nifedipine- and forskolin-induced mEPSCs. mEPSCs induced by norepinephrine had the same characteristics as those induced by forskolin [i.e. PKA-dependence and sensitivity to GABAB R and group III mGluR agonists, but not an A1 R agonist]. In summary, the present study highlights the differential effects of GABAB R, A1 R and mGluR agonists on glutamate release stimulated by different secretagogues, including the endogenous neuromodulator norepinephrine. These results suggest that the roles of these inhibitory GPCRs are not completely redundant, and also indicate the physiological implications of having different excitatory and inhibitory GPCRs on the same synapse.
authors.affiliation: Division of Biomedical Sciences, Memorial University, St John's, Newfoundland, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Muram
authors.affiliation: Division of Biomedical Sciences, Memorial University, St John's, Newfoundland, Canada.
authors.forename: T M
authors.initials: TM
authors.lastname: Rowe
authors.affiliation: Division of Biomedical Sciences, Memorial University, St John's, Newfoundland, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Hirasawa
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D013495:Supraoptic Nucleus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D018690:Excitatory Amino Acid Agonists; D058786:GABA-B Receptor Agonists; D043562:Receptors, G-Protein-Coupled; D005576:Colforsin; D018698:Glutamic Acid; D009543:Nifedipine; D009638:Norepinephrine
keywords: A1 receptors; GABAB receptors; magnocellular neurone; metabotropic glutamate receptors; patch clamp; synaptic modulation