cGMP-Dependent Protein Kinase II Modulates mPer1 and mPer2 Gene Induction and Influences Phase Shifts of the Circadian Clock

May 3, 2003Current biology : CB

cGMP-dependent protein kinase II affects mPer1 and mPer2 gene activity and changes the timing of the body’s internal clock

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Abstract

Mice lacking cGMP-dependent protein kinase II (cGKII) show defects in resetting their circadian clock after light exposure.

Circadian clock resetting was assessed through changes in wheel running activity following light pulses.
Light-induced expression of the mPer2 gene in the suprachiasmatic nuclei is significantly reduced in cGKII-deficient mice during early night.
In contrast, induction of the mPer1 gene is elevated in the absence of cGKII.
The light induction of cfos and phosphorylation of CREB at serine 133 remains unaffected in cGKII-deficient mice.
cGKII is implicated in the mechanism of clock phase adjustment, affecting the balance of mPer1 and mPer2 gene induction.

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BACKGROUND: In mammals, the master circadian clock that drives many biochemical, physiological, and behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Generation and maintenance of circadian rhythmicity rely on complex interlocked transcriptional/translational feedback loops involving a set of clock genes. Among the molecular components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) genes. Because the periodicity of the clock is not exactly 24 hr, it has to be adjusted periodically. The major stimulus for adjustment (resetting) of the clock is nocturnal light. It evokes activation of signaling pathways in the SCN that ultimately lead to expression of mPer1 and mPer2 genes conveying adjustment of the clock.

RESULTS: We show that mice deficient in cGMP-dependent protein kinase II (cGKII, also known as PKGII), despite regular retinal function, are defective in resetting the circadian clock, as assessed by changes in the onset of wheel running activity after a light pulse. At the molecular level, light induction of mPer2 in the SCN is strongly reduced in the early period of the night, whereas mPer1 induction is elevated in cGKII-deficient mice. Additionally, we show that light induction of cfos and light-dependent phosphorylation of CREB at serine 133 are not affected in these animals.

CONCLUSIONS: cGKII plays a role in the clock-resetting mechanism. In particular, the ability to delay clock phase is affected in cGKII-deficient mice. It seems that the signaling pathway involving cGKII influences in an opposite manner the light-induced induction of mPer1 and mPer2 genes and thereby influences the direction of a phase shift of the circadian clock.

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cGMP-Dependent Protein Kinase II Modulates mPer1 and mPer2 Gene Induction and Influences Phase Shifts of the Circadian Clock

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