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 AND 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.
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 AND 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.
Authors: Aziz Guellich; Shumin Gao; Chull Hong; Lin Yan; Thomas E Wagner; Sunil K Dhar; Bijan Ghaleh; Luc Hittinger; Kosaku Iwatsubo; Yoshihiro Ishikawa; Stephen F Vatner; Dorothy E Vatner Journal: Am J Physiol Heart Circ Physiol Date: 2010-06-18 Impact factor: 4.733
Authors: H Kirk Hammond; William F Penny; Jay H Traverse; Timothy D Henry; Matthew W Watkins; Clyde W Yancy; Ranya N Sweis; Eric D Adler; Amit N Patel; David R Murray; Robert S Ross; Valmik Bhargava; Alan Maisel; Denise D Barnard; N Chin Lai; Nancy D Dalton; Martin L Lee; Sanjiv M Narayan; Daniel G Blanchard; Mei Hua Gao Journal: JAMA Cardiol Date: 2016-05-01 Impact factor: 14.676
Authors: Wayne C H Wang; Susan H Pauer; Dan'elle C Smith; Madison A Dixon; David J Disimile; Alfredo Panebra; Steven S An; Blanca Camoretti-Mercado; Stephen B Liggett Journal: Am J Physiol Lung Cell Mol Physiol Date: 2014-09-26 Impact factor: 5.464