title: Regulation of gene transcription by voltage-gated L-type calcium channel, Cav1.3.
abstract: Cav1.3 L-type Ca(2+) channel is known to be highly expressed in neurons and neuroendocrine cells. However, we have previously demonstrated that the Cav1.3 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 Cav1.3 null mutant mouse model. Indeed, a recent study has confirmed the critical roles of Cav1.3 in the human heart (Baig, S. M., Koschak, A., Lieb, A., Gebhart, M., Dafinger, C., Nürnberg, G., Ali, A., Ahmad, I., Sinnegger-Brauns, M. J., Brandt, N., Engel, J., Mangoni, M. E., Farooq, M., Khan, H. U., Nürnberg, P., Striessnig, J., and Bolz, H. J. (2011) Nat. Neurosci. 14, 77-84). These studies suggest that detailed knowledge of Cav1.3 may have broad therapeutic ramifications in the treatment of cardiac arrhythmias. Here, we tested the hypothesis that there is a functional cross-talk between the Cav1.3 channel and a small conductance Ca(2+)-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 Cav1.3 may translocate to the nucleus where it functions as a transcriptional factor. Here, we reported for the first time that the C terminus of Cav1.3 translocates to the nucleus where it functions as a transcriptional regulator to modulate the function of Ca(2+)-activated K(+) channels in atrial myocytes. Nuclear translocation of the C-terminal domain of Cav1.3 is directly regulated by intracellular Ca(2+). Utilizing a Cav1.3 null mutant mouse model, we demonstrate that ablation of Cav1.3 results in a decrease in the protein expression of myosin light chain 2, which interacts and increases the membrane localization of SK2 channels.
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616,; the College of Life Sciences, Nanjing Normal University, Nanjing 210046, China. Electronic address: linglu@njnu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616.
authors.forename: Padmini
authors.initials: P
authors.lastname: Sirish
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Woltz
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616.
authors.forename: Valeriy
authors.initials: V
authors.lastname: Timofeyev
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616,; the Department of Veterans Affairs, Northern California Health Care System, Mather, California 95655.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Knowlton
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: the Department of Physiology, School of Medicine, University of Nevada, Reno, Nevada 89557, and. Electronic address: enyamoah@gmail.com.
authors.forename: Ebenezer N
authors.initials: EN
authors.lastname: Yamoah
authors.affiliation: From the Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California 95616,; the Department of Veterans Affairs, Northern California Health Care System, Mather, California 95655,. Electronic address: nchiamvimonvat@ucdavis.edu.
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D024722:Cardiac Myosins / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D018994:Myosin Light Chains / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C472073:CACNA1D protein, human; C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D018994:Myosin Light Chains; C107184:myosin light chain 2; D024722:Cardiac Myosins
keywords: Calcium Channel; Ion Channel; Potassium Channel; Transcription; Transcription Factor