title: CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway.
abstract: The heterodimerized transcription factors CLOCK-BMAL1 regulate the cardiomyocyte circadian rhythms. The L-type calcium currents play important role in the cardiac electrogenesis and arrhythmogenesis. Whether and how the CLOCK-BMAL1 regulate the cardiac L-type calcium channels are yet to be determined. The functions of the L-type calcium channels were evaluated with patch clamping techniques. Recombinant adenoviruses of CLOCK and BMAL1 were used in the expression experiments. We reported that the expressions and functions of CACNA1C (the α-subunit of the L-type calcium channels) showed circadian rhythms, with the peak at zeitgeber time 3 (ZT3). The endocardial action potential durations 90 (APD90) were correspondingly longer at ZT3. The protein levels of the phosphorylated Akt at threonine 308 (pAkt T308) also showed circadian rhythms. Overexpressions of CLOCK-BMAL1 significantly reduced the levels of CACNA1C while increasing the levels of pAkt T308 and pik3r1. Furthermore, the inhibitory effects of CLOCK-BMAL1 on CACNA1C could be abolished by the Akt inhibitor MK2206 or the PDK1 inhibitor GSK2334470. Collectively, our findings suggested that the expressions of the cardiac CACNA1C were under the CLOCK-BMAL1 regulation, probably through the PI3K-Akt signal pathway.
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.|b Department of Cardiology, Wuhan Asia Heart Hospital, Hubei, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Didi
authors.initials: D
authors.lastname: Zhu
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Han
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Qian
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Hou
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.affiliation: a Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Zou
mesh_terms: D056930:ARNTL Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D056926:CLOCK Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000502:physiology*; D006168:Guinea Pigs; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D056930:ARNTL Transcription Factors; D056926:CLOCK Proteins; D020746:Calcium Channels, L-Type; D006575:Heterocyclic Compounds, 3-Ring; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; C555257:GSK 2334470; C548887:MK 2206
keywords: BMAL1; CLOCK; L-type calcium currents; PI3K-Akt pathway; arythmie ventriculaire; cardiomyocyte action potentials; circadian rhythm; courants calciques de type L; potentiels d’action de cardiomyocytes; rythme circadian; ventricular arrhythmia; voie de signalization PI3K-Akt