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Developing Pharmacological Probes Targeting exchange protein directly activated by cAMP
Author(s) -
Cheng Xiaodong,
Tsalkova Tamara,
Mei Fang
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.656.3
Subject(s) - guanine nucleotide exchange factor , second messenger system , gene isoform , protein kinase a , cyclic adenosine monophosphate , intracellular , microbiology and biotechnology , signal transduction , biology , receptor , kinase , chemistry , biochemistry , gene
Cyclic adenosine monophosphate (cAMP), a prototypical second messenger, regulates a myriad of important biological processes under both physiological and pathological conditions, including cancer, diabetes, heart failure, and neurological disorders. In eukaryotic cells, the effects of cAMP are transduced by two intracellular cAMP receptors, the classic protein kinase A (PKA) and the more recently discovered exchange proteins directly activated by cAMP (EPACs) or cAMP‐regulated guanine nucleotide exchange factors (cAMP‐GEFs). Like PKA, EPACs contain a cAMP‐binding domain, an evolutionally conserved structural motif that acts as a molecular switch for sensing intracellular second messenger cAMP levels. Depending upon the specific cellular context, EPAC and PKA can act antagonistically or synergistically in controlling various cellular functions. Recent studies have demonstrated that levels of EPAC1 expression are increased in tumors of pancreatic cancer patients and in cardiac tissue of individuals with failing hearts while EPAC2 is important for insulin secretion and for cognitive function and may play a significant role in the development of diabetes and Alzheimer's disease. Unfortunately, there are no isoform‐selective EPAC small compounds available for dissecting the physiological functions of EPAC isoforms in normal and disease states. To bridge this major gap in our knowledge, we have developed isoform‐specific EPAC pharmacological probes. These EPAC‐specific probes are complementary to our genetic approaches using knockout mice models and will be powerful pharmacological tools for elucidating the functions of EPAC isoforms in various diseases and for testing the therapeutic potential of treating cancer or diabetes by specifically targeting EPAC/cAMP‐signaling components.