TY - JOUR
T1 - Sustained β1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway
AU - Wang, Wang
AU - Zhu, Weizhong
AU - Wang, Shiqiang
AU - Yang, Dongmei
AU - Crow, Michael T.
AU - Xiao, Rui Ping
AU - Cheng, Heping
PY - 2004/10/15
Y1 - 2004/10/15
N2 - A tenet of β1-adrenergic receptor (β1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in β1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, β1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding β1AR signaling in chronic heart failure.
AB - A tenet of β1-adrenergic receptor (β1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in β1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term β1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) β1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, β1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding β1AR signaling in chronic heart failure.
KW - Ca/calmodulin- dependent
KW - Cardiac contractility
KW - Phospholamban
KW - Protein kinase II
KW - cAMP-dependent protein kinase
KW - β-adrenergic receptor
UR - http://www.scopus.com/inward/record.url?scp=6344258936&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=6344258936&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000145361.50017.aa
DO - 10.1161/01.RES.0000145361.50017.aa
M3 - Article
C2 - 15375008
AN - SCOPUS:6344258936
SN - 0009-7330
VL - 95
SP - 798
EP - 806
JO - Circulation research
JF - Circulation research
IS - 8
ER -