Small molecule AKAP-Protein Kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes

Frank Christian, Márta Szaszák, Sabine Friedl, Stephan Drewianka, Dorothea Lorenz, Andrey Goncalves, Jens Furkert, Carolyn Vargas, Peter Schmieder, Frank Götz, Kerstin Zühlke, Marie Moutty, Hendrikje Göttert, Mangesh Joshi, Bernd Reif, Hannelore Haase, Ingo Morano, Solveig Grossmann, Anna Klukovits, Judit VerliRóbert Gáspár, Claudia Noack, Martin Bergmann, Robert Kass, Kornelia Hampel, Dmitry Kashin, Hans Gottfried Genieser, Friedrich W. Herberg, Debbie Willoughby, Dermot M.F. Cooper, George S. Baillie, Miles D. Houslay, Jens Peter Von Kries, Bastian Zimmermann, Walter Rosenthal, Enno Klussmann

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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, FMPAPI-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.

Original languageEnglish
Pages (from-to)9079-9096
Number of pages18
JournalJournal of Biological Chemistry
Volume286
Issue number11
DOIs
StatePublished - 18 Mar 2011
Externally publishedYes

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