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 Nat 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 ((R(p))-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.