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Am J Physiol Heart Circ Physiol 290: H1165-H1171, 2006. First published October 21, 2005; doi:10.1152/ajpheart.00821.2005
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Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes

Jacob Tfelt-Hansen,1,3,4 Jakob Lerche Hansen,2,3 Sanela Smajilovic,1,3 Ernest F. Terwilliger,5 Stig Haunso,1,3 and Soren P. Sheikh2,3

1Laboratory of Molecular Cardiology and 2Laboratory of Molecular and Cellular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen; 3Copenhagen Heart Arrhythmia Research Center, Copenhagen, Denmark; 4Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Membrane Biology Program, Brigham and Women's Hospital and Harvard Medical School, Boston; and 5Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine, Boston, Massachusetts

Submitted 3 August 2005 ; accepted in final form 18 October 2005

Both intra- and extracellular calcium play multiple roles in the physiology and pathophysiology of cardiomyocytes, especially in stimulus-contraction coupling. The intracellular calcium level is closely controlled through the concerted actions of calcium channels, exchangers, and pumps; however, the expression and function(s) of the so-called calcium-sensing receptor (CaR) in the heart remain less well characterized. The CaR is a seven-transmembrane receptor, which, in response to noncovalent binding of extracellular calcium, activates intracellular effectors, including G proteins and extracellular signal-regulated kinases (ERK1/2). We have shown that cultured neonatal cardiomyocytes express the CaR messenger RNA and the CaR protein. Furthermore, increasing concentrations of extracellular calcium and a type II CaR activator "calcimimetic" caused inositol phosphate (IP) accumulation, downregulated tritiated thymidine incorporation, and supported ERK1/2 phosphorylation, suggesting that the CaR protein is functionally active. Interestingly, the calcimimetic induced a more rapid ERK1/2 phosphorylation than calcium and left-shifted the IP concentration-response curve for extracellular calcium, supporting the hypothesis that CaR is functionally expressed in cardiac myocytes. This notion was underscored by studies using a virus containing a dominant-negative CaR construct, because this protein blunted the calcium-induced IP response. In conclusion, we have shown that the CaR is functionally expressed in neonatal ventricular cardiomyocytes and that the receptor activates second messenger pathways, including IP and ERK, and decreases DNA synthesis. A specific calcium-sensing receptor on cardiac myocytes could play a role in regulating cardiac development, function, and homeostasis.

calcium-sensing receptor; DNA synthesis; extracellular signal-regulated kinase 1/2; inositol phosphate; G protein-coupled receptor; seven-transmembrane receptor


Address for reprint requests and other correspondence: J. Tfelt-Hansen, Laboratory of Molecular Cardiology, Dept. of Cardiology, Univ. of Copenhagen, 20 Juliane Maries Vej, Section 9312, DK 2100 Copenhagen O, Denmark (e-mail: tfelt{at}dadlnet.dk)




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