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| Item Type: | Article |
|---|---|
| Title: | Small molecule AKAP/PKA interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes |
| Creators Name: | Christian, F., Szaszak, M., Friedl, S., Drewianka, S., Lorenz, D., Goncalves, A., Furkert, J., Vargas, C., Schmieder, P., Goetz, F., Zuehlke, K., Moutty, M., Goettert, H., Joshi, M., Reif, B., Haase, H., Morano, I., Grossmann, S., Klukovits, A., Verli, J., Gaspar, R., Noack, C., Bergmann, M., Kass, R., Hampel, K., Kashin, D., Genieser, H.G., Herberg, F.W., Willoughby, D., Cooper, D.M., Baillie, G.S., Houslay, M.D., von Kries, J.P., Zimmermann, B., Rosenthal, W. and Klussmann, E. |
| Abstract: | A-kinase anchoring proteins (AKAPs) tether protein kinase A (PKA) and other signaling proteins to defined intracellular sites, thereby establishing compartmentalized cAMP signaling. AKAP-PKA interactions play key roles in various cellular processes including the regulation of cardiac myocyte contractility. We discovered small molecules, FMP-API-1 and its derivatives, which inhibit AKAP-PKA interactions in vitro and in cultured cardiac myocytes. The molecules bind to an allosteric site of regulatory subunits of PKA identifying a hitherto unrecognized region that controls AKAP-PKA interactions. FMP-API-1 also activates PKA. The net effect of FMP-API-1 is a selective interference with compartmentalized cAMP signaling. In cardiac myocytes, FMP-API-1 reveals a novel mechanism involved in terminating beta-adrenoceptor-induced cAMP synthesis. In addition, FMP-API-1 leads to an increase in contractility of cultured rat cardiac myocytes and intact hearts. Thus FMP-API-1 represents not only a novel means to study compartmentalized cAMP/PKA signaling but, due to its effects on cardiac myocytes and intact hearts, provides the basis for a new concept in the treatment of chronic heart failure. |
| Keywords: | Adenylate Cyclase (Adenylyl Cyclase), Cyclic AMP (cAMP), Protein Kinase A (PKA), Protein Phosphorylation, Protein-Protein Interactions, Signal Transduction, AKAP, Compartmentalized Signaling, AKAP18, Yotiao, AKAP150, Compartmentalization, Animals, Rats |
| Source: | Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Volume: | 286 |
| Number: | 11 |
| Page Range: | 9079-9096 |
| Date: | 18 March 2011 |
| Official Publication: | https://doi.org/10.1074/jbc.M110.160614 |
| PubMed: | View item in PubMed |
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