Affiliation:
1. From the Departments of Medicine, VAMC-San Diego and University of California San Diego, and Department of Anesthesiology (D.M.R.), University of California San Diego, La Jolla, Calif.
Abstract
Background
—The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the β-adrenergic receptor (βAR) is a key determinant of a cell’s response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of βAR number, increases responsiveness to catecholamine stimulation in vivo.
Methods and Results
—Transgenic mice with cardiac-directed expression of AC
VI
showed increased transgene AC expression but no change in myocardial βAR number or G-protein content. When stimulated through the βAR, cardiac function was increased, and cardiac myocytes showed increased cAMP production. In contrast, basal cAMP and cardiac function were normal, and long-term transgene expression was not associated with abnormal histological findings or deleterious changes in cardiac function.
Conclusions
—The amount of AC sets a limit on cardiac β-adrenergic signaling in vivo, and increased AC, independent of βAR number and G-protein content, provides a means to regulate cardiac responsiveness to βAR stimulation. Overexpressing an effector (AC) does not alter transmembrane signaling except when receptors are activated, in contrast to receptor/G-protein overexpression, which yields continuous activation and has detrimental consequences. Our findings establish the importance of AC content in modulating β-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to βAR stimulation.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
160 articles.
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