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

J Biol Chem. 2011 Mar 18;286(11):9079-96. doi: 10.1074/jbc.M110.160614. Epub 2010 Dec 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Allosteric Regulation / drug effects
  • Allosteric Regulation / genetics
  • Animals
  • Chronic Disease
  • Cyclic AMP / genetics
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Heart Failure / drug therapy
  • Heart Failure / metabolism
  • Male
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Inbred WKY
  • Second Messenger Systems / drug effects
  • Second Messenger Systems / physiology*

Substances

  • A Kinase Anchor Proteins
  • Protein Kinase Inhibitors
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases