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.
Herrero
I
I
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, Madrid E-28040, Spain. jspieto@eucmax.sim.ucm.es
Sánchez-Prieto
J
J
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D002540:Cerebral Cortex / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D005971:Glutamates / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials; D009411:Nerve Endings / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D026941:Sodium Channel Blockers; D013574:Synaptosomes; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
D005971:Glutamates; D011943:Receptors, Adrenergic, beta; D026941:Sodium Channel Blockers; D005576:Colforsin; D016718:Arachidonic Acid; D013779:Tetrodotoxin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol