DOI: 10.1161/01.res.88.3.291. AKAP-Mediated Targeting of Protein Kinase A Regulates Contractility in Cardiac Myocytes

AKAP-Mediated Targeting of Protein Kinase A Regulates Contractility in Cardiac Myocytes

10.1161/01.res.88.3.291

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Circulation Research (276)

Abstract

Abstract —Compartmentalization of cAMP-dependent protein kinase A (PKA) by A-kinase anchoring proteins (AKAPs) targets PKA to distinct subcellular locations in many cell types. However, the question of whether AKAP-mediated PKA anchoring in the heart regulates cardiac contractile function has not been addressed. We disrupted AKAP-mediated PKA anchoring in cardiac myocytes by introducing, via adenovirus-mediated gene transfer, Ht31, a peptide that binds the PKA regulatory subunit type II (RII) with high affinity. This peptide competes with endogenous AKAPs for RII binding. Ht31P (a proline-substituted derivative), which does not bind RII, was used as a negative control. We then investigated the effects of Ht31 expression on RII distribution, Ca 2+ cycling, cell shortening, and PKA-dependent substrate phosphorylation. By confocal microscopy, we showed redistribution of RII from the perinuclear region and from periodic transverse striations in Ht31P-expressing cells to a diffuse cytosolic localization in Ht31-expressing cells. In the presence of 10 nmol/L isoproterenol, Ht31-expressing myocytes displayed an increased rate and amplitude of cell shortening and relaxation compared with control cells (uninfected and Ht31P-expressing myocytes); with isoproterenol stimulation we observed decreased time to 90% decline in Ca 2+ but no significant difference between Ht31-expressing and control cells in the rate of Ca 2+ cycling or amplitude of the Ca 2+ transient. The increase in PKA-dependent phosphorylation of troponin I and myosin binding protein C on isoproterenol stimulation was significantly reduced in Ht31-expressing cells compared with controls. Our results demonstrate that, in response to β-adrenergic stimulation, cardiomyocyte function and substrate phosphorylation by PKA is regulated by targeting of PKA by AKAPs.

Bibliography

Fink, M. A., Zakhary, D. R., Mackey, J. A., Desnoyer, R. W., Apperson-Hansen, C., Damron, D. S., & Bond, M. (2001). AKAP-Mediated Targeting of Protein Kinase A Regulates Contractility in Cardiac Myocytes. Circulation Research, 88(3), 291â297.

Authors 7

Mary A. Fink (first)
Daniel R. Zakhary (additional)
Julie A. Mackey (additional)
Russell W. Desnoyer (additional)
Carolyn Apperson-Hansen (additional)
Derek S. Damron (additional)
Meredith Bond (additional)

References 40 Referenced 107

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Dates

Type	When
Created	13 years, 2 months ago (June 11, 2012, 8:52 p.m.)
Deposited	1 year, 3 months ago (May 12, 2024, 4:22 p.m.)
Indexed	1 year ago (Aug. 13, 2024, 10:10 p.m.)
Issued	24 years, 6 months ago (Feb. 16, 2001)
Published	24 years, 6 months ago (Feb. 16, 2001)
Published Print	24 years, 6 months ago (Feb. 16, 2001)

Funders 0

None

BibTeX

@article{Fink_2001, title={AKAP-Mediated Targeting of Protein Kinase A Regulates Contractility in Cardiac Myocytes}, volume={88}, ISSN={1524-4571}, url={http://dx.doi.org/10.1161/01.res.88.3.291}, DOI={10.1161/01.res.88.3.291}, number={3}, journal={Circulation Research}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Fink, Mary A. and Zakhary, Daniel R. and Mackey, Julie A. and Desnoyer, Russell W. and Apperson-Hansen, Carolyn and Damron, Derek S. and Bond, Meredith}, year={2001}, month=feb, pages={291–297} }

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