(Circulation. 2000;101:1459.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Regulation of PKA Binding to AKAPs in the Heart
Alterations in Human Heart Failure
From the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio (D.R.Z., C.S.M., M.B.); and the Department of Molecular Cardiology (D.R.Z., M.B.), Lerner Research Institute, and Center for Anesthesiology Research (C.S.M.), Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Meredith Bond, PhD, Department of Molecular Cardiology, NB50, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail bondm{at}ccf.org
Background—cAMP-dependent protein kinase (PKA) regulates a broad range of cellular responses in the cardiac myocyte. Downstream regulation of the PKA pathway is mediated by a class of scaffolding proteins called A-kinase anchoring proteins (AKAPs), which sequester PKA to specific subcellular locations through binding to its regulatory subunit (R). However, the effect of RII autophosphorylation on AKAP binding and the degree of RII autophosphorylation in failing and nonfailing human hearts remains unknown.
Methods and Results—We investigated AKAP-RII binding by overlay
analysis and surface plasmon resonance spectroscopy and
measured RII autophosphorylation in human hearts by
backphosphorylation. Binding of Ht31 peptide
(representing the RII-binding region of AKAPs) to cardiac
RII was increased 
145% (P<0.01) for
autophosphorylated RII relative to
unphosphorylated control. By surface plasmon resonance,
RII autophosphorylation significantly increased binding
affinity to Ht31 by 200% (P<0.01). Baseline
PKA-dependent phosphorylation of RII was significantly
decreased 30% (P<0.05) in human hearts with dilated
cardiomyopathy compared with nonfailing
controls.
Conclusions—These results suggest that AKAP binding of PKA in the heart is regulated by RII autophosphorylation. Therefore AKAP targeting of PKA may be reduced in patients with end-stage heart failure. This mechanism may be responsible for the decreased cAMP-dependent phosphorylation of proteins in dilated cardiomyopathy that we and others have previously observed.
Key Words: cardiomyopathy • enzymes • proteins • spectroscopy
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