Small molecule AKAP/PKA interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes
Authors
- 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
Journal
- Journal of Biological Chemistry
Citation
- J Biol Chem 286 (11): 9079-9096
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.