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urn:hdl:2445/181261 β-Adrenergic receptors activate exchange protein directly activated by cAMP (Epac), translocate Munc13-1, and enhance the Rab3A-RIM1α interaction to potentiate glutamate release at cerebrocortical nerve terminal Ferrero, Jose J. Alvarez, Ana M. Ramírez-Franco, Jorge Godino, María C. Bartolomé-Martín, David Aguado, Carolina Torres, Magdalena Luján, Rafael Ciruela Alférez, Francisco Sánchez-Prieto, José Receptors adrenèrgics Nervis Proteïnes Adrenaline receptors Nerves Proteins The 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. 2021-11-16T16:43:05Z 2021-11-16T16:43:05Z 2013-10-25 2021-11-16T16:43:06Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1074/jbc.M113.463877 Journal of Biological Chemistry, 2013, vol. 288, num. 43, p. 31370-31385 https://doi.org/10.1074/jbc.M113.463877 (c) American Society for Biochemistry and Molecular Biology, 2013 info:eu-repo/semantics/openAccess American Society for Biochemistry and Molecular Biology Articles publicats en revistes (Patologia i Terapèutica Experimental)