RT Journal Article
T1 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
A1 Ferrero, José Javier
A1 Alvarez, Ana Maria
A1 Ramírez-Franco, Jorge
A1 Godino, Maria del Carmen
A1 Bartolomé-Martín, David
A1 Aguado, Carolina
A1 Torres Molina, Magdalena Isabel
A1 Luján, Rafael
A1 Ciruela, Francisco
A1 Sánchez-Prieto Borja, José
AB 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.
PB American Society for Biochemistry and Molecular Biology
SN 0021-9258
YR 2013
FD 2013
LK https://hdl.handle.net/20.500.14352/129940
UL https://hdl.handle.net/20.500.14352/129940
LA eng
NO 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.
NO 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)
NO Ministerio de Educación y Ciencia (España)
NO Instituto de Salud Carlos III
NO Comunidad de Madrid
DS Docta Complutense
RD 13 ene 2026