cAMP-dependent facilitation of glutamate release by beta-adrenergic receptors in cerebrocortical nerve terminals.

We have investigated the presence of a cAMP-protein kinase A-dependent pathway in cerebrocortical nerve terminals and its role in the modulation of glutamate release. The activation of adenylyl cyclase with forskolin enhances intrasynaptosomal cAMP and induces Ca2+-dependent glutamate release. The membrane permeant analogue dibutyryl cAMP mimics this facilitatory effect, whereas the inactive compound 1,9-dideoxyforskolin is without effect. This cAMP-induced facilitation is consistent with the induction of spontaneous action potentials that are abolished by the Na+ channel blocker tetrodotoxin and by reducing nerve terminal excitability with arachidonic acid. We have also demonstrated that a beta-adrenergic receptor is linked to this pathway because isoproterenol increases cAMP levels and glutamate release, and both actions are antagonized by the receptor antagonist propanolol and the protein kinase A inhibitors H89 and 8-chloroadenosine 3',5'-monophosphorothioate ((Rp)-isomer). The finding that the increase in cytoplasmic free Ca2+ concentration induced by synaptic activity reduces the concentration of agonist required to maximally activate adenylyl cyclase suggests that this enzyme may act as a coincidence detector, integrating glutamatergic neurotransmission and noradrenaline release.