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Small molecule AKAP/PKA interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes

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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. and Szaszak, M. and Friedl, S. and Drewianka, S. and Lorenz, D. and Goncalves, A. and Furkert, J. and Vargas, C. and Schmieder, P. and Goetz, F. and Zuehlke, K. and Moutty, M. and Goettert, H. and Joshi, M. and Reif, B. and Haase, H. and Morano, I. and Grossmann, S. and Klukovits, A. and Verli, J. and Gaspar, R. and Noack, C. and Bergmann, M. and Kass, R. and Hampel, K. and Kashin, D. and Genieser, H.G. and Herberg, F.W. and Willoughby, D. and Cooper, D.M. and Baillie, G.S. and Houslay, M.D. and von Kries, J.P. and Zimmermann, B. and 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 (U.S.A.)
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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