2026-06-28T10:21:38Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1299402026-01-13T01:17:30Zcom_20.500.14352_14col_20.500.14352_15

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 terminals Ferrero, José Javier Alvarez, Ana Maria Ramírez-Franco, Jorge Godino, Maria del Carmen Bartolomé-Martín, David Aguado, Carolina Torres Molina, Magdalena Isabel Luján, Rafael Ciruela, Francisco Sánchez-Prieto Borja, José Becas: AF2011-24779 y CSD2008-00005 (Francisco Ciruela) y CONSOLIDER (CSD2008-00005) (Rafael Luján y Francisco Ciruela) AM-I2M2 2011-BMD-2349 (José Sánchez Prieto y Magdalena Torres) The adenylyl cyclase activator forskolin facilitates synaptic transmission presynaptically via cAMP-dependent protein kinase (PKA). In addition, cAMP also increases glutamate release via PKA-independent mechanisms, although the downstream presynaptic targets remain largely unknown. Here, we describe the isolation of a PKA-independent component of glutamate release in cerebrocortical nerve terminals after blocking Na+ channels with tetrodotoxin. We found that 8-pCPT-2′-O-Me-cAMP, a specific activator of the exchange protein directly activated by cAMP (Epac), mimicked and occluded forskolin-induced potentiation of glutamate release. This Epac-mediated increase in glutamate release was dependent on phospholipase C, and it increased the hydrolysis of phosphatidylinositol 4,5-bisphosphate. Moreover, the potentiation of glutamate release by Epac was independent of protein kinase C, although it was attenuated by the diacylglycerol-binding site antagonist calphostin C. Epac activation translocated the active zone protein Munc13-1 from soluble to particulate fractions; it increased the association between Rab3A and RIM1α and redistributed synaptic vesicles closer to the presynaptic membrane. Furthermore, these responses were mimicked by the β-adrenergic receptor (βAR) agonist isoproterenol, consistent with the immunoelectron microscopy and immunocytochemical data demonstrating presynaptic expression of βARs in a subset of glutamatergic synapses in the cerebral cortex. Based on these findings, we conclude that βARs couple to a cAMP/Epac/PLC/Munc13/Rab3/RIM-dependent pathway to enhance glutamate release at cerebrocortical nerve terminals. Background: G protein-coupled receptors generating cAMP at nerve terminals modulate neurotransmitter release. Results: β-Adrenergic receptor enhances glutamate release via Epac protein activation and Munc13-1 translocation at cerebrocortical nerve terminals. Conclusion: Protein kinase A-independent signaling pathways triggered by β-adrenergic receptors control presynaptic function. Significance: β-Adrenergic receptors target presynaptic release machinery. 2026-01-12T17:31:23Z 2026-01-12T17:31:23Z 2013 journal article Ferrero JJ, Alvarez AM, Ramírez-Franco J, Godino MC, Bartolomé-Martín D, Aguado C, Torres M, Luján R, Ciruela F, Sánchez-Prieto J. 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 terminals. J Biol Chem. 2013 Oct 25;288(43):31370-85. 0021-9258 10.1074/jbc.M113.463877 https://hdl.handle.net/20.500.14352/129940 1083-351X https://doi.org/10.1074/jbc.M113.463877 24036110 eng info:eu-repo/grantAgreement/MICINN//BFU2010-16947/ES/CONTROL BIDIRECCIONAL DE LA LIBERACION DE GLUTAMATO POR EL RECEPTOR METABOTROPICO MGLUR7/ info:eu-repo/grantAgreement/MSC//RD06%2F0026%2F0016/ES/RED NEUROVASCULAR (RENEVAS)/ info:eu-repo/grantAgreement/MINECO//RD12%2F0014%2F0007/ES/Enfermedades vasculares cerebrales (Ictus)/ http://creativecommons.org/licenses/by/4.0/ open access Attribution 4.0 International American Society for Biochemistry and Molecular Biology