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Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation
Viacheslav O Nikolaev1, Alexey Moshkov, Alexander R Lyon
1Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Science (New York, N.Y.)
|February 27, 2010
Summary
Beta-adrenergic receptors (betaARs) in heart cells control cardiac function. In heart failure, beta2ARs move, altering cyclic adenosine monophosphate (cAMP) signals and potentially worsening the condition.
Area of Science:
- Cardiology
- Molecular Cell Biology
- Biophysics
Background:
- Beta1- and beta2-adrenergic receptors (betaARs) regulate cardiomyocyte function and heart failure development via cyclic adenosine monophosphate (cAMP).
- The precise spatial localization and functional significance of betaARs within cardiomyocytes have remained largely undetermined.
- betaARs are coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins).
Purpose of the Study:
- To investigate the spatial distribution of beta1- and beta2-adrenergic receptors (betaARs) in cardiomyocytes.
- To elucidate the functional implications of betaAR localization on cyclic adenosine monophosphate (cAMP) signaling.
- To examine changes in betaAR localization and cAMP signaling in a model of chronic heart failure.
Main Methods:
- Utilized nanoscale live-cell scanning ion conductance microscopy.
- Employed fluorescence resonance energy transfer (FRET) microscopy.
- Studied cardiomyocytes from healthy adult rats and mice, as well as a rat model of chronic heart failure.
Main Results:
- In healthy cardiomyocytes, beta2AR-induced cAMP signals were confined to deep transverse tubules, while beta1ARs were distributed broadly.
- In heart failure model cardiomyocytes, beta2ARs redistributed from transverse tubules to the cell crest.
- This redistribution resulted in diffuse, rather than localized, receptor-mediated cAMP signaling.
Conclusions:
- Spatial localization of betaARs is critical for compartmentalized cAMP signaling in cardiomyocytes.
- Redistribution of beta2ARs in heart failure alters cAMP compartmentation.
- Altered beta2AR localization and cAMP signaling may contribute to the failing myocardial phenotype.
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