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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Li, Sheng Chepurny, Oleg G. Liu, Tong Cheng, Xiaodong Tsalkova, Tamara Woods, Virgil L. Mei, Fang C. Leech, Colin A. Holz, George G. |
| Description | Author Affiliation: Tsalkova T ( Department of Pharmacology and Toxicology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.); |
| Abstract | The major physiological effects of cAMP in mammalian cells are transduced by two ubiquitously expressed intracellular cAMP receptors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), as well as cyclic nucleotide-gated ion channels in certain tissues. Although a large number of PKA inhibitors are available, there are no reported EPAC-specific antagonists, despite extensive research efforts. Here we report the identification and characterization of noncyclic nucleotide EPAC antagonists that are exclusively specific for the EPAC2 isoform. These EAPC2-specific antagonists, designated as ESI-05 and ESI-07, inhibit Rap1 activation mediated by EAPC2, but not EPAC1, with high potency in vitro. Moreover, ESI-05 and ESI-07 are capable of suppressing the cAMP-mediated activation of EPAC2, but not EPAC1 and PKA, as monitored in living cells through the use of EPAC- and PKA-based FRET reporters, or by the use of Rap1-GTP pull-down assays. Deuterium exchange mass spectroscopy analysis further reveals that EPAC2-specific inhibitors exert their isoform selectivity through a unique mechanism by binding to a previously undescribed allosteric site: the interface of the two cAMP binding domains, which is not present in the EPAC1 isoform. Isoform-specific EPAC pharmacological probes are highly desired and will be valuable tools for dissecting the biological functions of EPAC proteins and their roles in various disease states. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 45 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Benzene Derivatives Pharmacology Cyclic AMP Metabolism Guanine Nucleotide Exchange Factors Antagonists & Inhibitors Sulfones Animals Deuterium Exchange Measurement Enzyme Activation Drug Effects HEK293 Cells Mice Protein Isoforms Rap1 GTP-Binding Proteins Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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