title: Regulation of glutamatergic neurotransmission in the striatum by presynaptic adenylyl cyclase-dependent processes.
abstract: The aim here was to examine the possible roles of adenylyl cyclase- and protein kinase A (PKA)-dependent processes in ionotropic glutamate receptor (iGluR)-mediated neurotransmission using superfused mouse striatal slices and a non-metabolized L-glutamate analogue, D-[3H]aspartate. The direct and indirect presynaptic modulation of glutamate release and its susceptibility to changes in the intracellular levels of cyclic AMP (cAMP), Ca(2+) and calmodulin (CaM) and in protein phosphorylation was characterized by pharmacological manipulations. The agonists of iGluRs, 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate, stimulated the basal release of D-[3H]aspartate, while N-methyl-D-aspartate (NMDA) was without effect. Both the AMPA- and kainate-mediated responses were accentuated by the beta-adrenoceptor agonist isoproterenol. These facilitatory effects were mimicked by the permeable cAMP analogue dibutyryl-cAMP. The beta-adrenoceptor antagonist propranolol, the adenylyl cyclase inhibitor MDL12,330A, the inhibitor of PKA and PKC, H-7, and the PKA inhibitor H-89 abolished the isoproterenol effect on the kainate-evoked release. The dibutyryl-cAMP-induced potentiation was also attenuated by H-7. Isoproterenol, propranolol and MDL12,330A failed to affect the basal release of D-[3H]aspartate, but dibutyryl-cAMP was inhibitory and MDL12,330A activatory. In Ca(2+)-free medium, the kainate-evoked release was enhanced, being further accentuated by the CaM antagonists calmidazolium and trifluoperazine, though these inhibited the basal release. The potentiating effect of calmidazolium on the kainate-stimulated release was counteracted by both MDL12,330A and H-7. We conclude that AMPA- and kainate-evoked glutamate release from striatal glutamatergic terminals is potentiated by beta-adrenergic receptor-mediated adenylyl cyclase activation and cAMP accumulation. Glutamate release is enhanced if the Ca(2+)- and CaM-dependent, kainate-evoked processes do not prevent the excessive accumulation of intracellular cAMP.
authors.affiliation: Brain Research Center, University of Tampere Medical School, Tampere, Finland. lorodo@uta.fi
authors.forename: Róbert
authors.initials: R
authors.lastname: Dohovics
authors.forename: Réka
authors.initials: R
authors.lastname: Janáky
authors.forename: Vince
authors.initials: V
authors.lastname: Varga
authors.forename: András
authors.initials: A
authors.lastname: Hermann
authors.forename: Pirjo
authors.initials: P
authors.lastname: Saransaari
authors.forename: Simo S
authors.initials: SS
authors.lastname: Oja
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000502:physiology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005246:Feedback; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007097:Imines / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011433:Propranolol / Q000494:pharmacology; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology*; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000502:physiology; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D013449:Sulfonamides; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014268:Trifluoperazine / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases; D000319:Adrenergic beta-Antagonists; D003994:Bucladesine; D002118:Calcium; D002147:Calmodulin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D007093:Imidazoles; D007097:Imines; D007527:Isoenzymes; D007545:Isoproterenol; D007546:Isoquinolines; D007608:Kainic Acid; D016202:N-Methylaspartate; D009419:Nerve Tissue Proteins; D011433:Propranolol; D018091:Receptors, AMPA; D011943:Receptors, Adrenergic, beta; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D017661:Receptors, Presynaptic; D013449:Sulfonamides; D014268:Trifluoperazine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C031938:calmidazolium; C014925:RMI 12330A; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide