TY - JOUR
T1 - Small molecule AKAP-Protein Kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes
AU - Christian, Frank
AU - Szaszák, Márta
AU - Friedl, Sabine
AU - Drewianka, Stephan
AU - Lorenz, Dorothea
AU - Goncalves, Andrey
AU - Furkert, Jens
AU - Vargas, Carolyn
AU - Schmieder, Peter
AU - Götz, Frank
AU - Zühlke, Kerstin
AU - Moutty, Marie
AU - Göttert, Hendrikje
AU - Joshi, Mangesh
AU - Reif, Bernd
AU - Haase, Hannelore
AU - Morano, Ingo
AU - Grossmann, Solveig
AU - Klukovits, Anna
AU - Verli, Judit
AU - Gáspár, Róbert
AU - Noack, Claudia
AU - Bergmann, Martin
AU - Kass, Robert
AU - Hampel, Kornelia
AU - Kashin, Dmitry
AU - Genieser, Hans Gottfried
AU - Herberg, Friedrich W.
AU - Willoughby, Debbie
AU - Cooper, Dermot M.F.
AU - Baillie, George S.
AU - Houslay, Miles D.
AU - Von Kries, Jens Peter
AU - Zimmermann, Bastian
AU - Rosenthal, Walter
AU - Klussmann, Enno
PY - 2011/3/18
Y1 - 2011/3/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79953189372&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.160614
DO - 10.1074/jbc.M110.160614
M3 - Article
C2 - 21177871
AN - SCOPUS:79953189372
SN - 0021-9258
VL - 286
SP - 9079
EP - 9096
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -