Transcription factors Csx/Nkx2.5 and GATA4 distinctly regulate expression of Ca2+ channels in neonatal rat heart.

The cardiac transcription factors Csx/Nkx2.5 and GATA4 play important roles in vertebrate heart development. Although mutations of Csx/Nkx2.5 or GATA4 are associated with various congenital heart diseases, their mechanism of action on cardiomyocyte function is not completely elucidated. In this study, we therefore investigated the actions of these transcription factors on the electrophysiological features and expression of ion channels in cardiomyocytes. Genes for transcription factors Csx/Nkx2.5 and GATA4 were transfected into rat neonatal cardiomyocytes by adenoviral infection. Action potentials, L-, T-type Ca(2+) channels and hyperpolarization-activated cation current (I(h)) of rat neonatal myocytes were recorded by patch clamp technique after adenoviral infection. Expression of ion channels was confirmed by real-time PCR. In Csx/Nkx2.5 overexpression myocytes, the spontaneous beating rate was markedly increased with an up-regulation of the Ca(v)3.2 T-type Ca(2+) channel, while in GATA4 overexpression myocytes, the T-type Ca(2+) channel was unchanged. On the other hand, the L-type Ca(2+) channel was down-regulated by both Csx/Nkx2.5 and GATA4 overexpression; the level of Ca(v)1.3 mRNA was dramatically decreased by Csx/Nkx2.5 overexpression. These results indicate that Csx/Nkx2.5 and GATA4 play important roles on the generation of pacemaker potentials modulating voltage-dependent Ca(2+) channels in the neonatal cardiomyocyte.