Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38 MAPK and modulation of Ca2+-dependent K+ channels in cerebellar neurons.
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.
Ster
Jeanne
J
Institute of Functional Genomics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5203, Institute National de la Santé et de la Recherche Médicale U661, Universités Montpellier I et II, 34095 Montpellier, France.
De Bock
Frédéric
F
Guérineau
Nathalie C
NC
Janossy
Andrea
A
Barrère-Lemaire
Stéphanie
S
Bos
Johannes L
JL
Bockaert
Joël
J
Fagni
Laurent
L
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D024681:Potassium Channels, Calcium-Activated; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium