Abstract
BackgroundThe role played by calcium as a regulator of circadian rhythms is not well understood. The effect of the pharmacological inhibition of the ryanodine receptor (RyR), inositol 1,4,5-trisphosphate receptor (IP3R), and endoplasmic-reticulum Ca2+-ATPase (SERCA), as well as the intracellular Ca2+-chelator BAPTA-AM was explored on the 24-h rhythmicity of the liver-clock protein PER1 in an experimental model of circadian synchronization by light and restricted-feeding schedules.MethodsLiver explants from Period1-luciferase (Per1-luc) transgenic rats with either free food access or with a restricted meal schedule were treated for several days with drugs to inhibit the activity of IP3Rs (2-APB), RyRs (ryanodine), or SERCA (thapsigargin) as well as to suppress intracellular calcium fluctuations (BAPTA-AM). The period of Per1-luc expression was measured during and after drug administration.ResultsLiver explants from rats fed ad libitum showed a lengthened period in response to all the drugs tested. The pharmacological treatments of the explants from meal-entrained rats induced the same pattern, with the exception of the ryanodine treatment which, unexpectedly, did not modify the Per1-luc period. All effects associated with drug application were reversed after washout, indicating that none of the pharmacological treatments was toxic to the liver cultures.ConclusionsOur data suggest that Ca2+ mobilized from internal deposits modulates the molecular circadian clock in the liver of rats entrained by light and by restricted meal access.
Highlights
The role played by calcium as a regulator of circadian rhythms is not well understood
2-aminoethoxydiphenyl borate (2-APB) altered the period of Per1-luc expression in liver explants from ad libitum (AL) and FR rats 2-APB is commonly used as an inhibitor of IP3Rs [25,31]
As was the case with BAPTA-AM and thapsigargin, exposure of liver explants from both AL and FR rats to 2-APB significantly lengthened the period of Per1-luc expression (Figure 5A; AL = 27.7 ± 0.6 h and FR = 27.9 ± 0.3 h vs. dimethyl sulfoxide (DMSO); Bonferroni post-test p < 0.001; Figure 5B)
Summary
The role played by calcium as a regulator of circadian rhythms is not well understood. It is well established that restricted feeding synchronizes rhythmic processes through activation of a food-entrainable oscillator (FEO). Activation of the FEO influences specific brain areas related to feeding and metabolic control [8] and peripheral tissues such as the liver, which displays a rapid and robust phase shift in response to food entrainment in many physiological and metabolic hepatic functions [9,10,11,12]. Notable changes in 24-h variations in the amplitude of free fatty acid concentrations, stomach content, and hepatic triacylglyceride levels have been reported in FR protocols [13,14,15] It has not been reported if meal entrainment causes modifications in the free-running period of rhythmic parameters
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