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CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway.
- Source :
-
Canadian journal of physiology and pharmacology [Can J Physiol Pharmacol] 2016 Sep; Vol. 94 (9), pp. 1023-32. Date of Electronic Publication: 2016 May 04. - Publication Year :
- 2016
-
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.
- Subjects :
- ARNTL Transcription Factors antagonists & inhibitors
Action Potentials physiology
Animals
CLOCK Proteins antagonists & inhibitors
Cells, Cultured
Guinea Pigs
Heterocyclic Compounds, 3-Ring pharmacology
Indazoles pharmacology
Myocytes, Cardiac physiology
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Pyrimidines pharmacology
ARNTL Transcription Factors physiology
CLOCK Proteins physiology
Calcium Channels, L-Type metabolism
Circadian Rhythm physiology
Phosphatidylinositol 3-Kinases metabolism
Protein Subunits metabolism
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1205-7541
- Volume :
- 94
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Canadian journal of physiology and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 27376484
- Full Text :
- https://doi.org/10.1139/cjpp-2015-0398