Regulation of Gene Transcription by Voltage-gated L-type Calcium Channel, Cav1.3

Ca(v)1.3 L-type Ca2+ channel is known to be highly expressed in neurons and neuroendocrine cells. However, we have previously demonstrated that the Ca(v)1.3 channel is also expressed in atria and pacemaking cells in the heart. The significance of the tissue-specific expression of the channel is underpinned by our previous demonstration of atrial fibrillation in a Ca(v)1.3 null mutant mouse model. Indeed, a recent study has confirmed the critical roles of Ca(v)1.3 in the human heart (Baig, S. M., Koschak, A., Lieb, A., Gebhart, M., Dafinger, C., Nuberg, G., Ali, A., Ahmad, I., Sinnegger-Brauns, M. J., Brandt, N., Engel, J., Mangoni, M. E., Farooq, M., Khan, H. U., Nuberg, P., Striessnig, J., and Bolz, H. J. (2011) Nat. Neurosci. 14, 77-84). These studies suggest that detailed knowledge of Ca(v)1.3 may have broad therapeutic ramifications in the treatment of cardiac arrhythmias. Here, we tested the hypothesis that there is a functional crosstalk between the Ca(v)1.3 channel and a small conductance Ca2+ activated K+ channel (SK2), which we have documented to be highly expressed in human and mouse atrial myocytes. Specifically, we tested the hypothesis that the C terminus of Ca(v)1.3 may translocate to the nucleus where it functions as a transcriptional factor. Here, we reported for the first time that the C terminus of Ca(v)1.3 translocates to the nucleus where it functions as a transcriptional regulator to modulate the function of Ca2+-activated K+ channels in atrial myocytes. Nuclear translocation of the C-terminal domain of Ca(v)1.3 is directly regulated by intracellular Ca2+. Utilizing a Ca(v)1.3 null mutant mouse model, we demonstrate that ablation of Ca(v)1.3 results in a decrease in the protein expression of myosin light chain 2, which interacts and increases the membrane localization of SK2 channels.