Abstract
Recently, we reported that homozygous deletion of alternative exon 33 of Ca(V)1.2 calcium channel in the mouse resulted in ventricular arrhythmias arising from increased Ca(V)1.2(Δ33) I(CaL) current density in the cardiomyocytes. We wondered whether heterozygous deletion of exon 33 might produce cardiac phenotype in a dose-dependent manner, and whether the expression levels of RNA splicing factors known to regulate alternative splicing of exon 33 might change in human heart failure. Unexpectedly, we found that exon 33(+/-) cardiomyocytes showed similar Ca(V)1.2 channel properties as wild-type cardiomyocyte, even though Ca(V)1.2(Δ33) channels exhibit a gain-in-function. In human hearts, we found that the mRNA level of splicing factor Rbfox1, but not Rbfox2, was downregulated in dilated cardiomyopathy, and CACNA1C mRNA level was dramatically decreased in the both of dilated and ischemic cardiomyopathy. These data imply Rbfox1 may be involved in the development of cardiomyopathies via regulating the alternative splicing of Ca(V)1.2 exon 33. (149 words).