Small molecule AKAP/PKA interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes
F. Christian; M. Szaszak; S. Friedl; S. Drewianka; D. Lorenz; A. Goncalves; J. Furkert;C. Vargas; P. Schmieder; F. Goetz; K. Zuehlke; M. Moutty; H. Goettert; M. Joshi; B. Reif; H. Haase; I. Morano; S. Grossmann; A. Klukovits; J. Verli; R. Gaspar; C. Noack; M. Bergmann; R. Kass; K. Hampel; D. Kashin; H.G. Genieser; F.W. Herberg; D. Willoughby; D.M. Cooper; G.S. Baillie; M.D. Houslay; J.P. von Kries; B. Zimmermann; W. Rosenthal; E. Klussmann*
J. Biol. Chem. 286, 9079-9096 (2011)
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.