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Christian, F.* ; Szaszák, M.* ; Friedl, S.* ; Drewianka, S.* ; Lorenz, D.* ; Goncalves, A.* ; Furkert, J.* ; Vargas, C.* ; Schmieder, P.* ; Götz, F.* ; Zühlke, K.* ; Moutty, M.* ; Göttert, H.* ; Joshi, M.* ; Reif, B.* ; Haase, H.* ; Morano, I.* ; Grossmann, S.* ; Klukovits, A.* ; Verli, J.* ; Gáspár, R.* ; Noack, C.* ; Bergmann, M.* ; Kass, R.* ; Hampel, K.* ; Kashin, D.* ; Genieser, H.G.* ; Herberg, F.W.* ; Willoughby, D.* ; Cooper, D.M.* ; Baillie, G.S.* ; Houslay, M.D.* ; von Kries, J.P.* ; Zimmermann, B.* ; Rosenthal, W.* ; Klussmann, E.*

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

J. Biol. Chem. 286, 9079-9096 (2011)
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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, 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Quellenangaben Band: 286, Heft: 11, Seiten: 9079-9096 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Begutachtungsstatus Peer reviewed