© 2000 American Heart Association, Inc.
Cellular Biology |
Coupling Function of Endogenous 
1- and ß-Adrenergic Receptors in Mouse Cardiomyocytes
From the Departments of Pharmacology (A.S., E.P., S.A.A., S.F.S.) and Medicine (S.F.S.), College of Physicians and Surgeons, Columbia University, New York, NY; and Department of Microbiology, University of Illinois at Urbana-Champaign (B.A.W.).
Correspondence to Susan F. Steinberg, MD, Associate Professor of Pharmacology and Medicine, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W 168 St, New York, NY 10032. E-mail sfs1{at}columbia.edu
Abstract—Genetically altered
mouse models constitute unique systems to delineate the role of
adrenergic receptor (AR) signaling mechanisms as modulators of
cardiomyocyte function. The interpretation of results from
these models depends on knowledge of the signaling properties of
endogenous ARs in mouse cardiomyocytes. In the
present study, we identify for the first time several defects in AR
signaling in cardiomyocytes cultured from mouse ventricles.
ß1-ARs induce robust increases in cAMP accumulation and
the amplitude of the calcium and cell motion transients in mouse
cardiomyocytes. Selective ß2-AR stimulation
increases the amplitude of calcium and motion transients, with only a
trivial rise in cAMP accumulation in comparison. ß2-AR
responses are not influenced by pertussis toxin in cultured mouse
cardiomyocytes. 
1-ARs fail to
activate phospholipase C, the extracellular signal–regulated
protein kinase, p38-MAPK, or stimulate hypertrophy in mouse
cardiomyocytes. Control experiments establish that this is
not due to a lesion in distal elements in the signaling machinery,
because these responses are induced by protease-activated
receptor-1 agonists and phospholipase C is activated by
Pasteurella multocida toxin (a Gq
-subunit agonist). Surprisingly, norepinephrine
activates p38-MAPK via ß-ARs in mouse
cardiomyocytes, but ß-AR activation of p38-MAPK alone is
not sufficient to induce cardiomyocyte
hypertrophy. Collectively, these results identify a
generalized defect in 1-AR signaling and a defect in
ß2-AR linkage to cAMP (although not to an inotropic
response) in cultured mouse cardiomyocytes. These naturally
occurring vagaries in AR signaling in mouse cardiomyocytes
provide informative insights into the requirements for hypertrophic
signaling and impact on the value of mouse cardiomyocytes
as a reconstitution system to investigate AR signaling in the
heart.
Key Words: receptors, adrenergic • cardiomyocytes • cAMP • phospholipase C • mitogen-activated protein kinases
This article has been cited by other articles:
 |
|
 |
|
  T. Bupha-Intr, J. W. Holmes, and P. M. L. Janssen Induction of hypertrophy in vitro by mechanical loading in adult rabbit myocardium Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3759 - H3767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wenzel, Y. Abdallah, S. Helmig, C. Schafer, H. M. Piper, and K.-D. Schluter Contribution of PI 3-kinase isoforms to angiotensin II- and {alpha}-adrenoceptor-mediated signalling pathways in cardiomyocytes Cardiovasc Res, July 15, 2006; 71(2): 352 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Garcia, T. Shah, and J. Garcia Immunolocalization of type 2 inositol 1,4,5-trisphosphate receptors in cardiac myocytes from newborn mice Am J Physiol Cell Physiol, October 1, 2004; 287(4): C1048 - C1057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Barki-Harrington, C. Perrino, and H. A Rockman Network integration of the adrenergic system in cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 391 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. B. Roman, P. H. Goldspink, E. Spaite, D. Urboniene, R. McKinney, D. L. Geenen, R. J. Solaro, and P. M. Buttrick Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2089 - H2095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sabri, S. G. Alcott, H. Elouardighi, E. Pak, C. Derian, P. Andrade-Gordon, K. Kinnally, and S. F. Steinberg Neutrophil Cathepsin G Promotes Detachment-induced Cardiomyocyte Apoptosis via a Protease-activated Receptor-independent Mechanism J. Biol. Chem., June 20, 2003; 278(26): 23944 - 23954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. O. Rybin, E. Pak, S. Alcott, and S. F. Steinberg Developmental Changes in {beta}2-Adrenergic Receptor Signaling in Ventricular Myocytes: the Role of Gi proteins and Caveolae Microdomains Mol. Pharmacol., June 1, 2003; 63(6): 1338 - 1348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sabri, J. Guo, H. Elouardighi, A. L. Darrow, P. Andrade-Gordon, and S. F. Steinberg Mechanisms of Protease-activated Receptor-4 Actions in Cardiomyocytes. ROLE OF Src TYROSINE KINASE J. Biol. Chem., March 21, 2003; 278(13): 11714 - 11720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bartel, E.-G. Krause, G. Wallukat, and P. Karczewski New insights into {beta}2-adrenoceptor signaling in the adult rat heart Cardiovasc Res, March 1, 2003; 57(3): 694 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Michelotti, M. J. Bauman, M. P. Smith, and D. A. Schwinn Cloning and Characterization of the Rat alpha 1a-Adrenergic Receptor Gene Promoter. DEMONSTRATION OF CELL SPECIFICITY AND REGULATION BY HYPOXIA J. Biol. Chem., February 28, 2003; 278(10): 8693 - 8705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lavoie, J.-F. Mercier, A. Salahpour, D. Umapathy, A. Breit, L.-R. Villeneuve, W.-Z. Zhu, R.-P. Xiao, E. G. Lakatta, M. Bouvier, et al. beta 1/beta 2-Adrenergic Receptor Heterodimerization Regulates beta 2-Adrenergic Receptor Internalization and ERK Signaling Efficacy J. Biol. Chem., September 13, 2002; 277(38): 35402 - 35410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.-P. Xiao {beta}-Adrenergic Signaling in the Heart: Dual Coupling of the {beta}2-Adrenergic Receptor to Gs and Gi Proteins Sci. Signal., October 16, 2001; 2001(104): re15 - re15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rapacciuolo, G. Esposito, K. Caron, L. Mao, S. A. Thomas, and H. A. Rockman Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy J. Am. Coll. Cardiol., September 1, 2001; 38(3): 876 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-T. TSENG, R. KOPEL, J. P. STABILA, B. G. MCGONNIGAL, T. T. NGUYEN, P. A. GRUPPUSO, and J. F. PADBURY {beta}-Adrenergic receptors ({beta}AR) regulate cardiomyocyte proliferation during early postnatal life FASEB J, September 1, 2001; 15(11): 1921 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Devic, Y. Xiang, D. Gould, and B. Kobilka beta -Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from beta 1 and beta 2 Adrenoceptor Knockout Mice Mol. Pharmacol., September 1, 2001; 60(3): 577 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Steinberg G protein-coupled receptor kinases: gotta real kure for heart failure? J. Am. Coll. Cardiol., August 1, 2001; 38(2): 541 - 545. [Full Text] [PDF]
|
|
|
|
|
|
I. Lemire, A. Ducharme, J.-C. Tardif, F. Poulin, L. R. Jones, B. G. Allen, T. E. Hebert, and H. Rindt Cardiac-directed overexpression of wild-type {alpha}1B-adrenergic receptor induces dilated cardiomyopathy Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H931 - H938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Esposito, S. V. N. Prasad, A. Rapacciuolo, L. Mao, W. J. Koch, and H. A. Rockman Cardiac Overexpression of a Gq Inhibitor Blocks Induction of Extracellular Signal-Regulated Kinase and c-Jun NH2-Terminal Kinase Activity in In Vivo Pressure Overload Circulation, March 13, 2001; 103(10): 1453 - 1458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. F. Steinberg The Cellular Actions of {beta}-Adrenergic Receptor Agonists : Looking Beyond cAMP Circ. Res., December 8, 2000; 87(12): 1079 - 1082. [Full Text] [PDF]
|
|
|
|
|
|
X.-F. Deng, D. G. Rokosh, and P. C. Simpson Autonomous and Growth Factor-Induced Hypertrophy in Cultured Neonatal Mouse Cardiac Myocytes : Comparison With Rat Circ. Res., October 27, 2000; 87(9): 781 - 788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Sagi, T. M. Seasholtz, M. Kobiashvili, B. A. Wilson, D. Toksoz, and J. H. Brown Physical and Functional Interactions of Galpha q with Rho and Its Exchange Factors J. Biol. Chem., April 27, 2001; 276(18): 15445 - 15452. [Abstract] [Full Text] [PDF]
|
|