Small Molecule AKAP-Protein Kinase A (PKA) Interaction Disruptors That Activate PKA Interfere with Compartmentalized cAMP Signaling in Cardiac Myocytes

被引：81

作者：

Christian, Frank ^{[1
]}

Szaszak, Marta ^{[1
]}

Friedl, Sabine ^{[1
]}

Drewianka, Stephan ^{[2
]}

Lorenz, Dorothea ^{[1
]}

Goncalves, Andrey ^{[1
,3
]}

Furkert, Jens ^{[1
]}

Vargas, Carolyn ^{[1
]}

Schmieder, Peter ^{[1
]}

Goetz, Frank ^{[1
,3
]}

Zuehlke, Kerstin ^{[1
,3
]}

Moutty, Marie ^{[1
,3
]}

Goettert, Hendrikje ^{[1
]}

Joshi, Mangesh ^{[1
]}

Reif, Bernd ^{[1
]}

Haase, Hannelore ^{[3
]}

Morano, Ingo ^{[3
]}

Grossmann, Solveig ^{[1
]}

Klukovits, Anna ^{[4
]}

Verli, Judit ^{[4
]}

Robert Gaspar ^{[4
]}

Noack, Claudia ^{[3
]}

Bergmann, Martin ^{[3
]}

Kass, Robert ^{[5
]}

Hampel, Kornelia ^{[2
]}

Kashin, Dmitry ^{[6
]}

Genieser, Hans-Gottfried ^{[6
]}

Herberg, Friedrich W. ^{[7
]}

Willoughby, Debbie ^{[8
]}

Cooper, Dermot M. F. ^{[8
]}

Baillie, George S. ^{[9
]}

Houslay, Miles D. ^{[9
]}

von Kries, Jens Peter ^{[1
]}

Zimmermann, Bastian ^{[2
]}

Rosenthal, Walter ^{[3
,10
]}

Klussmann, Enno ^{[1
,3
]}

机构：

[1] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany

[2] Biaffin GmbH & Co KG, D-34132 Kassel, Germany

[3] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany

[4] Univ Szeged, Dept Pharmacodynam & Biopharm, H-6720 Szeged, Hungary

[5] Columbia Univ, Med Ctr, New York, NY 10032 USA

[6] Biol Life Sci Inst, D-28199 Bremen, Germany

[7] Univ Kassel, Dept Biochem, D-34109 Kassel, Germany

[8] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1PD, England

[9] Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland

[10] Charite, D-14195 Berlin, Germany

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2011年 / 286卷 / 11期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

RENAL PRINCIPAL CELLS; POTENTIAL-DRUG TARGETS; ANCHORING PROTEIN; REGULATORY SUBUNITS; SCAFFOLDING PROTEINS; POTASSIUM CHANNEL; ADENYLYL CYCLASES; CA(V)1.2 CHANNELS; TROPONIN-I; PHOSPHORYLATION;

D O I：

10.1074/jbc.M110.160614

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta-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.

引用

页码：9079 / 9096

页数：18

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