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EPAC proteins transduce diverse cellular actions of cAMP
Author(s) -
Borland Gillian,
Smith Brian O,
Yarwood Stephen J
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00087.x
Subject(s) - rap1 , guanine nucleotide exchange factor , microbiology and biotechnology , signal transduction , small gtpase , signalling , cyclic adenosine monophosphate , protein kinase a , gtpase , g protein , biology , effector , second messenger system , chemistry , kinase , receptor , biochemistry
It has now been over 10 years since efforts to completely understand the signalling actions of cAMP (3′‐5′‐cyclic adenosine monophosphate) led to the discovery of exchange protein directly activated by cAMP (EPAC) proteins. In the current review we will highlight important advances in the understanding of EPAC structure and function and demonstrate that EPAC proteins mediate multiple actions of cAMP in cells, revealing future targets for pharmaceutical intervention. It has been known for some time that drugs that elevate intracellular cAMP levels have proven therapeutic benefit for diseases ranging from depression to inflammation. The challenge now is to determine which of these positive actions of cAMP involve activation of EPAC‐regulated signal transduction pathways. EPACs are specific guanine nucleotide exchange factors for the Ras GTPase homologues, Rap1 and Rap2, which they activate independently of the classical routes for cAMP signalling, cyclic nucleotide‐gated ion channels and protein kinase A. Rather, EPAC activation is triggered by internal conformational changes induced by direct interaction with cAMP. Leading from this has been the development of EPAC‐specific agonists, which has helped to delineate numerous cellular actions of cAMP that rely on subsequent activation of EPAC. These include regulation of exocytosis and the control of cell adhesion, growth, division and differentiation. Recent work also implicates EPAC in the regulation of anti‐inflammatory signalling in the vascular endothelium, namely negative regulation of pro‐inflammatory cytokine signalling and positive support of barrier function. Further elucidation of these important signalling mechanisms will no doubt support the development of the next generation of anti‐inflammatory drugs.