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Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38 MAPK and modulation of Ca²⁺-dependent K⁺ channels in cerebellar neurons

Ster, Jeanne, De Bock, Frédéric, Guérineau, Nathalie C., Janossy, Andrea, Barrère-Lemaire, Stéphanie, Bos, Johannes L., Bockaert, Joël, Fagni, Laurent
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.7 pp. 2519-2524
calcium, cyclic AMP, guanosinetriphosphatase, mitogen-activated protein kinase, neurons, polypeptides, potassium channels, regulatory proteins
The exchange factor directly activated by cAMP (Epac) is a newly discovered direct target for cAMP and a guanine-nucleotide exchange factor for the small GTPase Rap. Little is known about the neuronal functions of Epac. Here we show that activation of Epac by specific cAMP analogs or by the pituitary adenylate cyclase-activating polypeptide induces a potent activation of the Ca²⁺-sensitive big K⁺ channel, slight membrane hyperpolarization, and increased after-hyperpolarization in cultured cerebellar granule cells. These effects involve activation of Rap and p38 MAPK, which mobilizes intracellular Ca²⁺ stores. These findings reveal a cAMP Epac-dependent and protein kinase A-independent signaling cascade that controls neuronal excitability.