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

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.; Klussmann, E.

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:	Christian, F., Szaszak, M., Friedl, S., Drewianka, S., Lorenz, D., Goncalves, A., Furkert, J., Vargas, C., Schmieder, P. ORCID: https://orcid.org/0000-0001-9968-9327, Goetz, F., Zuehlke, K., Moutty, M., Goettert, H., Joshi, M., Reif, B., Haase, H., Morano, I. ORCID: https://orcid.org/0000-0001-7315-2222, 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. ORCID: https://orcid.org/0000-0003-4716-4988, Zimmermann, B., Rosenthal, W. and Klussmann, E. ORCID: https://orcid.org/0000-0003-4004-5003
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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