Enhanced expression of L-type Cav1.3 calcium channels in murine embryonic hearts from Cav1.2-deficient mice

Voltage-gated calcium (Ca2+) channels play a key role in the control of heart contraction and are essential for normal heart development. The Ca(v)1.2 L-type calcium channel is the predominant isoform in cardiomyocytes and is essential for excitation-contraction coupling. Although the inactivation of the Ca(v)1.2 gene caused embryonic lethality before embryonic day E14.5, hearts were contracting before E14 depending on a dihydropyridine-sensitive calcium influx. We analyzed the consequences of the deletion of the Ca(v)1.2 channel on the expression level of other voltage-gated calcium channels in the embryonic mouse heart and isolated cardiomyocytes. A strong compensatory up-regulation of the Ca(v)1.3 calcium channel was observed on the mRNA as well as on the protein level. Reverse transcriptase PCR indicated that the recently identified new Ca(v)1.3(1b) isoform was strongly up-regulated, whereas a more moderate increase was found for the Ca(v)1.3(1a) variant. Heterologous expression of Ca(v)1.3( 1b) in HEK293 cells induced Ba2+ currents with properties similar to those found in Ca(v)1.2 (-/-) cardiomyocytes, suggesting that this isoform constitutes a major component of the residual L-type calcium current in Ca(v)1.2 (-/-) cardiomyocytes. In summary, our results imply that calcium channel expression is dynamically regulated during heart development and that the Ca(v)1.3 channel may substitute for Ca(v)1.2 during early embryogenesis.