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

Autor/innen

  • 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

Quellenangabe

  • J Biol Chem 286 (11): 9079-9096

Zusammenfassung

  • 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.


DOI

doi:10.1074/jbc.M110.160614