EPAC proteins transduce diverse cellular actions of cAMP

Borland, G., Smith, B.O. and Yarwood, S.J. (2009) EPAC proteins transduce diverse cellular actions of cAMP. British Journal of Pharmacology, 158(1), pp. 70-86. (doi: 10.1111/j.1476-5381.2008.00087.x)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Yarwood, Dr Stephen and Smith, Dr Brian and Borland, Dr Gillian
• Authors: Borland, G., Smith, B.O., and Yarwood, S.J.
• Subjects: Q Science > QH Natural history > QH301 Biology
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: British Journal of Pharmacology
• Journal Abbr.: BJP
• ISSN: 0007-1188
• ISSN (Online): 1476-5381
• Published Online: 06 February 2009