title: Small molecule AKAP-protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes.
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, 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.
authors.affiliation: Leibniz Institute for Molecular Pharmacology, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Christian
authors.forename: Márta
authors.initials: M
authors.lastname: Szaszák
authors.forename: Sabine
authors.initials: S
authors.lastname: Friedl
authors.forename: Stephan
authors.initials: S
authors.lastname: Drewianka
authors.forename: Dorothea
authors.initials: D
authors.lastname: Lorenz
authors.forename: Andrey
authors.initials: A
authors.lastname: Goncalves
authors.forename: Jens
authors.initials: J
authors.lastname: Furkert
authors.forename: Carolyn
authors.initials: C
authors.lastname: Vargas
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.forename: Frank
authors.initials: F
authors.lastname: Götz
authors.forename: Kerstin
authors.initials: K
authors.lastname: Zühlke
authors.forename: Marie
authors.initials: M
authors.lastname: Moutty
authors.forename: Hendrikje
authors.initials: H
authors.lastname: Göttert
authors.forename: Mangesh
authors.initials: M
authors.lastname: Joshi
authors.forename: Bernd
authors.initials: B
authors.lastname: Reif
authors.forename: Hannelore
authors.initials: H
authors.lastname: Haase
authors.forename: Ingo
authors.initials: I
authors.lastname: Morano
authors.forename: Solveig
authors.initials: S
authors.lastname: Grossmann
authors.forename: Anna
authors.initials: A
authors.lastname: Klukovits
authors.forename: Judit
authors.initials: J
authors.lastname: Verli
authors.forename: Róbert
authors.initials: R
authors.lastname: Gáspár
authors.forename: Claudia
authors.initials: C
authors.lastname: Noack
authors.forename: Martin
authors.initials: M
authors.lastname: Bergmann
authors.forename: Robert
authors.initials: R
authors.lastname: Kass
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hampel
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kashin
authors.forename: Hans-Gottfried
authors.initials: HG
authors.lastname: Genieser
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Herberg
authors.forename: Debbie
authors.initials: D
authors.lastname: Willoughby
authors.forename: Dermot M F
authors.initials: DM
authors.lastname: Cooper
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: von Kries
authors.forename: Bastian
authors.initials: B
authors.lastname: Zimmermann
authors.forename: Walter
authors.initials: W
authors.lastname: Rosenthal
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002908:Chronic Disease; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*
chemical_list: D054758:A Kinase Anchor Proteins; D047428:Protein Kinase Inhibitors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases