title: Ca2+-calmodulin-dependent protein kinase II represses cardiac transcription of the L-type calcium channel alpha(1C)-subunit gene (Cacna1c) by DREAM translocation.
abstract: Recent studies have demonstrated that changes in the activity of calcium-calmodulin-dependent protein kinase II (CaMKII) induce a unique cardiomyocyte phenotype through the regulation of specific genes involved in excitation-contraction (E-C)-coupling. To explain the transcriptional effects of CaMKII we identified a novel CaMKII-dependent pathway for controlling the expression of the pore-forming α-subunit (Cav1.2) of the L-type calcium channel (LTCC) in cardiac myocytes. We show that overexpression of either cytosolic (δC) or nuclear (δB) CaMKII isoforms selectively downregulate the expression of the Cav1.2. Pharmacological inhibition of CaMKII activity induced measurable changes in LTCC current density and subsequent changes in cardiomyocyte calcium signalling in less than 24 h. The effect of CaMKII on the α1C-subunit gene (Cacna1c) promoter was abolished by deletion of the downstream regulatory element (DRE), which binds transcriptional repressor DREAM/calsenilin/KChIP3. Imaging DREAM-GFP (green fluorescent protein)-expressing cardiomyocytes showed that CaMKII potentiates the calcium-induced nuclear translocation of DREAM. Thereby CaMKII increases DREAM binding to the DRE consensus sequence of the endogenous Cacna1c gene. By mathematical modelling we demonstrate that the LTCC downregulation through the Ca2+-CaMKII-DREAM cascade constitutes a physiological feedback mechanism enabling cardiomyocytes to adjust the calcium intrusion through LTCCs to the amount of intracellular calcium detected by CaMKII.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, Neulaniementie 2, FI-70211 Kuopio, Finland.
authors.forename: Jarkko J
authors.initials: JJ
authors.lastname: Ronkainen
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Hänninen
authors.forename: Topi
authors.initials: T
authors.lastname: Korhonen
authors.forename: Jussi T
authors.initials: JT
authors.lastname: Koivumäki
authors.forename: Reka
authors.initials: R
authors.lastname: Skoumal
authors.forename: Sini
authors.initials: S
authors.lastname: Rautio
authors.forename: Veli-Pekka
authors.initials: VP
authors.lastname: Ronkainen
authors.forename: Pasi
authors.initials: P
authors.lastname: Tavi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001596:Benzylamines / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D055724:Electrophysiological Phenomena / Q000502:physiology; D056966:Excitation Contraction Coupling / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D018408:Patch-Clamp Techniques; D017354:Point Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004247:DNA; D051605:Kv Channel-Interacting Proteins; D020097:Natriuretic Peptide, Brain; D012097:Repressor Proteins; D013449:Sulfonamides; C496756:Csen protein, mouse; C496760:Kcnip3 protein, rat; C419385:L-type calcium channel alpha(1C); C072105:KN 93; D000096926:Benzenesulfonamides