title: Presynaptic mGlu7 receptors control GABA release in mouse hippocampus.
abstract: The functional role of presynaptic release-regulating metabotropic glutamate type 7 (mGlu7) receptors in hippocampal GABAergic terminals was investigated. Mouse hippocampal synaptosomes were preloaded with [(3)H]D-γ-aminobutyric acid ([(3)H]GABA) and then exposed in superfusion to 12 mM KCl. The K(+)-evoked [(3)H]GABA release was inhibited by the mGlu7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082, 0.001-10 μM), as well as by the group III mGlu receptor agonist l-(+)-2-amino-4-phosphonobutyric acid [(l)-AP4, 0.01-1 mM]. The mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG, 10-100 nM] was ineffective. AMN082 and (l)-AP4-induced effects were recovered by the mGlu7 negative allosteric modulator (NAM) 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). AMN082 also inhibited in a MMPIP-sensitive manner the K(+)-evoked release of endogenous GABA. AMN082 and the adenylyl cyclase (AC) inhibitor MDL-12,330A reduced [(3)H]GABA exocytosis in a 8-Br-cAMP-sensitive. AMN082-inhibitory effect was additive to that caused by (-)baclofen, but insensitive to the GABA(B) antagonist 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid (CGP52432). Conversely, (-)baclofen-induced inhibition of GABA exocytosis was insensitive to MMPIP. Finally, the forskolin-evoked [(3)H]GABA release was reduced by AMN082 or (-)baclofen but abolished when the two agonists were added concomitantly. Mouse hippocampal synaptosomal plasmamembranes posses mGlu7 receptor proteins; confocal microscopy analysis unveiled that mGlu7 proteins colocalize with syntaxin-1A (Stx-1A), with vesicular GABA transporter (VGAT)-proteins and with GABA(B) receptor subunit proteins. We propose that presynaptic inhibitory mGlu7 heteroreceptors, negatively coupled to AC-dependent intraterminal pathway, exist in mouse hippocampal GABA-containing terminals, where they colocalize, but do not functionally cross-talk, with GABA(B) autoreceptors. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
authors.affiliation: Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, viale Cembrano 4, 16148 Genoa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Summa
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Prisco
authors.forename: Massimo
authors.initials: M
authors.lastname: Grilli
authors.forename: Cesare
authors.initials: C
authors.lastname: Usai
authors.forename: Mario
authors.initials: M
authors.lastname: Marchi
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007097:Imines / Q000494:pharmacology; D051379:Mice; D010721:Phosphinic Acids / Q000494:pharmacology; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D050827:Syntaxin 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C110733:3,4-dicarboxyphenylglycine; C553164:6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo(4,5-c)pyridin-4(5H)-one; D000067956:Adenylyl Cyclase Inhibitors; D000613:Aminobutyrates; D001559:Benzhydryl Compounds; D001565:Benzoates; D001596:Benzylamines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D007097:Imines; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D010721:Phosphinic Acids; D011728:Pyridones; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D050827:Syntaxin 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C102719:metabotropic glutamate receptor 7; C493406:vesicular GABA transporter; C083008:CGP 52432; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; C014925:RMI 12330A; D001418:Baclofen; C012729:2-amino-4-phosphonobutyric acid; D005998:Glycine