Regulation of glutamatergic neurotransmission in the striatum by presynaptic adenylyl cyclase-dependent processes

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.