help button home button Biophys. J.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Biophys. J. BioFAST: First Published February 9, 2007. doi:10.1529/biophysj.106.095356
© 2007 by the Biophysical Society.

A more recent version of this article appeared on May 1, 2007.
This Article
Right arrow Full Text (Rapid PDF)
Right arrow All Versions of this Article:
biophysj.106.095356v1
92/9/3317    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Iancu, R. V.
Right arrow Articles by Harvey, R. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iancu, R. V.
Right arrow Articles by Harvey, R. D.

CELL BIOPHYSICS

Compartmentation of cAMP Signaling in Cardiac Myocytes: A Computational Study

Radu V. Iancu 1, Stephen W. Jones 1 and Robert D. Harvey 1*

1 Case Western Reserve University

* To whom correspondence should be addressed. E-mail: rdh3{at}case.edu.

Submitted on August 17, 2006
Revised on October 2, 2006
Accepted on 17 January 2007


  Abstract
Receptor-mediated changes in cAMP production play an essential role in sympathetic and parasympathetic regulation of the electrical, mechanical, and metabolic activity of cardiac myocytes. However, responses to receptor activation cannot be easily ascribed to a uniform increase or decrease in cAMP activity throughout the entire cell. In the present study, we used a computational approach to test the hypothesis that in cardiac ventricular myocytes the effects of {beta}1-adrenergic receptor ({beta}1AR) and M2 muscarinic receptor (M2R) activation involve compartmentation of cAMP. A model consisting of two sub-membrane (caveolar and extra-caveolar) microdomains and one bulk cytosolic domain was created using published information on the location of {beta}1ARs and M2Rs, as well as the location of stimulatory (Gs) and inhibitory (Gi) G proteins, adenylyl cyclase isoforms inhibited (AC5/6) and stimulated (AC4/7) by Gi, and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that (1) bulk basal cAMP can be high (~1 µM) and only modestly stimulated by {beta}1AR activation (~2 µM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A (~100 nM to ~2 µM); (2) M2R activation strongly reduces the {beta}1AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and (3) during weak {beta}1AR stimulation, M2R activation not only reduces caveolar cAMP, but also produces a rebound increase in caveolar cAMP following termination of M2R activity. We conclude that compartmentation of cAMP can provide a quantitative explanation for several aspects of cardiac signaling.

Key Words: beta-adrenergic responses, cAMP, cardiac myocytes, cell signaling, compartmentation, muscarinic responses




This article has been cited by other articles:


Home page
 Am. J. Physiol. Cell Physiol.Home page
R. V. Iancu, G. Ramamurthy, S. Warrier, V. O. Nikolaev, M. J. Lohse, S. W. Jones, and R. D. Harvey
Cytoplasmic cAMP concentrations in intact cardiac myocytes
Am J Physiol Cell Physiol, August 1, 2008; 295(2): C414 - C422.
[Abstract] [Full Text] [PDF]

Home page
 JGPHome page
W. Xin, T. M. Tran, W. Richter, R. B. Clark, and T. C. Rich
Roles of GRK and PDE4 Activities in the Regulation of {beta}2 Adrenergic Signaling
J. Gen. Physiol., March 31, 2008; 131(4): 349 - 364.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
B.-G. Kerfant, D. Zhao, I. Lorenzen-Schmidt, L. S. Wilson, S. Cai, S. R. W. Chen, D. H. Maurice, and P. H. Backx
PI3K{gamma} Is Required for PDE4, not PDE3, Activity in Subcellular Microdomains Containing the Sarcoplasmic Reticular Calcium ATPase in Cardiomyocytes
Circ. Res., August 17, 2007; 101(4): 400 - 408.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Copyright © 2007 by the Biophysical Society.