Ferrero, Jose J.Alvarez, Ana M.Ramírez-Franco, JorgeGodino, María C.Bartolomé-Martín, DavidAguado, CarolinaTorres, MagdalenaLuján, RafaelCiruela Alférez, FranciscoSánchez-Prieto, José2021-11-162021-11-162013-10-250021-9258https://hdl.handle.net/2445/181261The adenylyl cyclase activator forskolin presynaptically facilitates synaptic transmission through cAMP-dependent protein kinase, PKA. However, cAMP also increases glutamate release via PKA-independent mechanisms, although the downstream presynaptic targets remain largely unknown. Here we found that a PKA-independent release component can be isolated in cerebrocortical nerve terminals after blocking Na+ channels with tetrodotoxin. 8-pCPT-2-O-Me-cAMP, 8pCPT, a specific activator of the exchange protein directly activated by cAMP, Epac, mimicks and occluded forskolin-induced release. The Epac mediated increase in release is dependent on phospholipase C, and increased phosphatidylinositol (4,5)-bisphosphate hydrolysis. Furthermore, the potentiation of release does not depend on protein kinase C, although it is reduced by the diacylglycerol-binding site antagonist calphostin C. Epac activation translocates the active zone protein Munc13-1 from soluble to particulate fractions, increases the association between Rab3A and Rim1αand redistributes synaptic vesicles to positions closer to the presynaptic membrane. We also found that the β-adrenergic receptor agonist, isoproterenol, mimicked all these responses consistent with high-resolution immunoelectron microscopy and immunocytochemical data showing presynaptic expression of the β-ARs at a subset of glutamatergic synapses of the cerebral cortex. It is concluded that β adrenergic receptors couple to a cAMP/Epac/PLC/Munc13/Rab3/Rim dependent pathway to enhance glutamate release at cerebrocortical nerve terminals.16 p.application/pdfeng(c) American Society for Biochemistry and Molecular Biology, 2013Receptors adrenèrgicsNervisProteïnesAdrenaline receptorsNervesProteinsinfo:eu-repo/semantics/article6288032021-11-16info:eu-repo/semantics/openAccess24036110