PMID- 15375008
OWN - NLM
STAT- MEDLINE
DCOM- 20050428
LR  - 20131121
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 95
IP  - 8
DP  - 2004 Oct 15
TI  - Sustained beta1-adrenergic stimulation modulates cardiac contractility by 
      Ca2+/calmodulin kinase signaling pathway.
PG  - 798-806
AB  - A tenet of beta1-adrenergic receptor (beta1AR) 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 beta1AR-stimulated cardiac apoptosis. In this 
      study, we determined roles of CaMKII and PKA in sustained versus short-term 
      beta1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. 
      Short-term (10-minute) and sustained (24-hour) beta1AR 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, 
      beta1AR 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 beta1AR signaling in chronic heart failure.
FAU - Wang, Wang
AU  - Wang W
AD  - Laboratory of Cardiovascular Sciences, National Institute on Aging, National 
      Institutes of Health, Baltimore, MD 21224, USA.
FAU - Zhu, Weizhong
AU  - Zhu W
FAU - Wang, Shiqiang
AU  - Wang S
FAU - Yang, Dongmei
AU  - Yang D
FAU - Crow, Michael T
AU  - Crow MT
FAU - Xiao, Rui-Ping
AU  - Xiao RP
FAU - Cheng, Heping
AU  - Cheng H
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040916
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Adrenergic alpha-Agonists)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Receptors, Adrenergic, beta-1)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (phospholamban)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - X4W3ENH1CV (Norepinephrine)
RN  - XM03YJ541D (Prazosin)
SB  - IM
MH  - Adrenergic alpha-Agonists/pharmacology
MH  - Animals
MH  - Calcium Signaling/drug effects/*physiology
MH  - Calcium-Binding Proteins/metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2
MH  - Calcium-Calmodulin-Dependent Protein Kinases/antagonists & 
      inhibitors/genetics/*physiology
MH  - Cell Size/drug effects
MH  - Cells, Cultured/drug effects/physiology
MH  - Cyclic AMP/*physiology
MH  - Cyclic AMP-Dependent Protein Kinases/*physiology
MH  - Humans
MH  - Male
MH  - Mutagenesis, Site-Directed
MH  - Myocardial Contraction/drug effects/*physiology
MH  - Myocytes, Cardiac/drug effects/physiology
MH  - Norepinephrine/pharmacology
MH  - Phosphorylation
MH  - Prazosin/pharmacology
MH  - Protein Processing, Post-Translational
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Adrenergic, beta-1/drug effects/*physiology
MH  - Recombinant Fusion Proteins/physiology
MH  - Second Messenger Systems/drug effects/*physiology
EDAT- 2004/09/18 05:00
MHDA- 2005/04/29 09:00
CRDT- 2004/09/18 05:00
PHST- 2004/09/18 05:00 [pubmed]
PHST- 2005/04/29 09:00 [medline]
PHST- 2004/09/18 05:00 [entrez]
AID - 01.RES.0000145361.50017.aa [pii]
AID - 10.1161/01.RES.0000145361.50017.aa [doi]
PST - ppublish
SO  - Circ Res. 2004 Oct 15;95(8):798-806. doi: 10.1161/01.RES.0000145361.50017.aa. 
      Epub 2004 Sep 16.