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

Cross-talk between metabotropic glutamate receptor 7 and beta adrenergic receptor signaling at cerebrocortical nerve terminals

“…β-ARs activate Gs proteins and increase cAMP levels. However, cAMPmediated enhancement of spontaneous release is not mediated by PKA, the classic presynaptic cAMP target (Herrero and Sánchez-Prieto, 1996;Castillo et al, 2002), but rather by the guanine nucleotide exchange factor, EPAC, which has emerged as a new alternative cAMP effector (Huang and Hsu, 2006;Gekel and Neher, 2008;Ferrero et al, 2013a). Indeed, EPAC activation mimics and occludes the isoproterenol-induced increase in spontaneous release.…”

“…Beta adrenergic receptors (β-ARs) are also expressed presynaptically in axons that establish asymmetric, putative glutamatergic synapses (Ferrero et al, 2013a), consistent with their role as heteroreceptors that enhance glutamate release (Huang et al, 1996;Kobayashi et al, 2009;Ferrero et al, 2013a). β-ARs activate Gs proteins and increase cAMP levels.…”

“…Many presynaptic G protein coupled receptors (GPCRs) inhibit release by reducing the activity of presynaptic Ca 2+ channels (Choi and Lovinger, 1996;Millán et al, 2002Millán et al, , 2003, yet GPCRs also modulate neurotransmitter release downstream of Ca 2+ channels by targeting proteins in the release machinery (Sakaba and Neher, 2003;Gerachshenko et al, 2005;Bauer et al, 2007; M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3 Pelkey et al, 2008;Nakajima et al, 2009;Martín et al, 2010;Zhang et al, 2011;Ferrero et al, 2013a).…”

“…Indeed, EPAC activation mimics and occludes the isoproterenol-induced increase in spontaneous release. Interestingly, β-AR and EPAC activation increases PIP 2 hydrolysis, and it provokes Munc13-1 translocation to the membrane (Ferrero et al, 2013a). In addition, EPAC also activates phospholipase C € (PLC € ), which can transduce signals from small GTPases through its Ras binding site (Schmidt et al, 2001;Branham et al, 2009;Dzhura et al, 2011).…”

Epac activation initiates associative odor preference memories in the rat pup

“…As mentioned in the Introduction, Epac can enhance presynaptic release of neurotransmitter. Indeed, Epac enhances Rab3A-RIM1 (proteins involved in transmitter release machinery) interactions through phospholipase C to potentiate glutamate release in cerebrocortical nerve terminals (Ferrero et al 2013). Epac also enhances intracellular calcium levels and has been shown to recruit calcium calmodulin kinase II (CAMKII), both of which promote neurotransmitter secretion in other systems (Mani et al 2014).…”