Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38 MAPK and modulation of Ca2+-dependent K+ channels in cerebellar neurons
- Jeanne Ster*,
- Frédéric De Bock*,
- Nathalie C. Guérineau*,
- Andrea Janossy*,
- Stéphanie Barrère-Lemaire*,
- Johannes L. Bos†,
- Joël Bockaert*, and
- Laurent Fagni*,‡
- *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; and
- †Department of Physiological Chemistry and Centre for Biochemical Genetics, University Medical Centre Utrecht Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
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Communicated by Jean-Pierre Changeux, Institut Pasteur, Paris, France, December 13, 2006 (received for review May 31, 2006)
Abstract
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.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: laurent.fagni{at}igf.cnrs.fr
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Author contributions: J.S., J.B., and L.F. designed research; J.S., F.D.B., N.C.G., A.J., and S.B.-L. performed research; J.L.B. contributed new reagents/analytic tools; J.S. and N.C.G. analyzed data; and J.S., J.B., and L.F. wrote the paper.
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The authors declare no conflict of interest.
- Abbreviations:
- 8-pCPT,
- 8-(4-chlorophenylthio)-2′-O-methyl-cAMP;
- BK,
- big K+;
- CGCs,
- cultured cerebellar granule cells;
- Epac,
- exchange factor directly activated by cAMP;
- IP3,
- inositol 1,4,5-trisphosphate;
- AHP,
- after-hyperpolarization;
- NPo,
- cumulated open probability;
- NT,
- nontransfected;
- PACAP,
- pituitary adenylate cyclase-activating polypeptide;
- PLC,
- phospholipase C;
- PKA,
- protein kinase A;
- GEF,
- guanine-nucleotide exchange factor.
- © 2007 by The National Academy of Sciences of the USA
