Christian, F. et al. (2011) Small molecule AKAP-protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes. Journal of Biological Chemistry, 286(11), pp. 9079-9096. (doi: 10.1074/jbc.M110.160614) (PMID:21177871) (PMCID:PMC305896)
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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, 3,3'-diamino-4,4'-dihydroxydiphenylmethane (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 β-adrenoreceptor-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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Houslay, Professor Miles and Baillie, Professor George and Christian, Dr Frank |
| Authors: | Christian, F., Szaszák, M., Friedl, S., Drewianka, S., Lorenz, D., Goncalves, A., Furkert, J., Vargas, C., Schmieder, P., Götz, F., Zühlke, K., Moutty, M., Göttert, H., Joshi, M., Reif, B., Haase, H., Morano, I., Grossmann, S., Klukovits, A., Verli, J., Gáspár, R., Noack, C., Bergmann, M., Kass, R., Hampel, K., Kashin, D., Genieser, H.-G., Herberg, F. W., Willoughby, D., Cooper, D. M.F., Baillie, G. S., Houslay, M. D., von Kries, J. P., Zimmermann, B., Rosenthal, W., and Klussmann, E. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
| Journal Name: | Journal of Biological Chemistry |
| Journal Abbr.: | J Biol Chem. |
| Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
| ISSN: | 0021-9258 |
| ISSN (Online): | 1083-351X |
| Published Online: | 22 December 2010 |
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