Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice.
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.


RESULTS
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.
Gao
M H
MH
Department of Medicine, VAMC-San Diego, Calif. 92161, USA.
Lai
N C
NC
Roth
D M
DM
Zhou
J
J
Zhu
J
J
Anzai
T
T
Dalton
N
N
Hammond
H K
HK
D000262:Adenylyl Cyclases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis; D004452:Echocardiography; D019204:GTP-Binding Proteins / Q000032:analysis; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000737:chemistry; D011943:Receptors, Adrenergic, beta / Q000032:analysis; D015398:Signal Transduction; D013268:Stimulation, Chemical; D019076:Transgenes
D002316:Cardiotonic Agents; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol