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CAR is a transmembrane protein of the Ig superfamily which serves as receptor for different adenoviruses. Due to the strong expression of CAR in brain and heart during embryonic development, the physiological function is of great interest. CAR knockout animal models show malformation of the heart which leads to death during development between days E11.5 and E13.5. This observation indicates an important function of CAR during heart development. Up to date, the cellular mechanism of CAR is not well understood. Therefore we studied the signaling pathway of CAR in cardiomyocytes and neurons. The Ad2 fiber knob is the binding part of the Ad2 adenovirus to CAR and it initiates the virus uptake. Here, we demonstrated in cardiomyocytes and neurons an increase in cytosolic Ca2+ concentration from intracellular Ca2+ stores upon application of the Ad2 fiber knob. Ad2 induced Ca2+ increase was blocked by wortmannin suggesting that CAR signaling triggers Ca2+ release from intracellular stores via PI3K. CAR knockout mice at E10.5 show a significant higher beating rate of the cardiomyocytes and Ca2+ transients compared to wild type. Further investigation of Ca2+ transients in CAR knockout cardiomyocytes revealed a significant faster calcium decline and decay time constant. Inhibition of SERCA2 by thapsigargin or CPA did not show the strong decrease in beating frequency in CAR knockout cardiomyocytes like observed in wild type cardiomyocytes. Therefore we suggest that in CAR knockout cardiomyocytes SERCA2 activity is enhanced.In summary, the homophilic cell adhesion protein CAR modulates the transfer and transmission of the cardiovascular excitation and muscle contraction between neighboring cardiomyocytes.