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1 Laboratory of Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Copenhagen Heart Arrhythmia Research Center (CHARC), Copenhagen, Denmark; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Membrane Biology Program,, Brigham and Womens Hospital and Harvard Medical School, Boston, USA
2 Laboratory of Molecular and Cellular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Copenhagen Heart Arrhythmia Research Center (CHARC), Copenhagen, Denmark
3 Laboratory of Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory of Molecular and Cellular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
4 Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Membrane Biology Program,, Brigham and Womens Hospital and Harvard Medical School, Boston, USA
5 Laboratory of Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Copenhagen Heart Arrhythmia Research Center (CHARC), Copenhagen, Denmark
* To whom correspondence should be addressed. E-mail: tfelt{at}dadlnet.dk.
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). Herein, we show that cultured neonatal cardiomyocytes express the CaR messenger RNA and the CaR protein. Furthermore, increasing concentrations of extracellular Ca2+ 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 Ca2+, 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, since this protein blunted the Ca2+-induced IP response. In conclusion, we show 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.
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