Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice.
Circulation
; 99(12): 1618-22, 1999 Mar 30.
Article
em En
| MEDLINE
| ID: mdl-10096940
ABSTRACT
BACKGROUND:
The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the beta-adrenergic receptor (betaAR) is a key determinant of a cell's response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of betaAR number, increases responsiveness to catecholamine stimulation in vivo. METHODS ANDRESULTS:
Transgenic mice with cardiac-directed expression of ACVI showed increased transgene AC expression but no change in myocardial betaAR number or G-protein content. When stimulated through the betaAR, 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 beta-adrenergic signaling in vivo, and increased AC, independent of betaAR number and G-protein content, provides a means to regulate cardiac responsiveness to betaAR 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 beta-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to betaAR stimulation.
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Base de dados:
MEDLINE
Assunto principal:
Catecolaminas
/
Adenilil Ciclases
/
Coração
Idioma:
En
Ano de publicação:
1999
Tipo de documento:
Article