(Circulation. 1999;99:1618-1622.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Adenylylcyclase Increases Responsiveness to Catecholamine Stimulation in Transgenic Mice
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.
Correspondence to H. Kirk Hammond, MD (111-A), VAMC-San Diego, 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail khammond{at}ucsd.edu
Background—The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the ß-adrenergic receptor (ßAR) is a key determinant of a cell's response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of ßAR number, increases responsiveness to catecholamine stimulation in vivo.
Methods and Results—Transgenic mice with cardiac-directed expression of ACVI showed increased transgene AC expression but no change in myocardial ßAR number or G-protein content. When stimulated through the ßAR, 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 ß-adrenergic signaling in vivo, and increased AC, independent of ßAR number and G-protein content, provides a means to regulate cardiac responsiveness to ßAR 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 ß-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to ßAR stimulation.
Key Words: receptors, adrenergic, beta • proteins • adenylylcyclase
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