Ferrero, José JavierAlvarez, Ana MariaRamírez-Franco, JorgeGodino, Maria del CarmenBartolomé-Martín, DavidAguado, CarolinaTorres Molina, Magdalena IsabelLuján, RafaelCiruela, FranciscoSánchez-Prieto Borja, José2026-01-122026-01-122013Ferrero 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):31370-85.0021-925810.1074/jbc.M113.463877https://hdl.handle.net/20.500.14352/129940Becas: 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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article1083-351Xhttps://doi.org/10.1074/jbc.M113.46387724036110open access612.8.015Cyclic AMP (cAMP)G Protein-coupled Receptors (GPCR)Neurotransmitter ReleasePhospholipase CSynaptosomesEpac ProteinsMunc13–1RIM1αRab3ANeurociencias (Biológicas)2490.02 Neuroquímica