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The Journal of Neuroscience, November 5, 2003, 23(31):10021-10031

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Cellular/Molecular
Are Changes in MAPK/ERK Necessary or Sufficient for Entrainment in Chick Pineal Cells?

Geetha Yadav,¹ Martin Straume,² James Heath, III,¹ and Martin Zatz¹

¹Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-4068, and ²Center for Biomathematical Technology, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22903

Chick pineal cells in culture display a circadian rhythm of melatonin release. Light pulses can entrain (phase shift) the rhythm. One candidate for the photoentrainment pathway uses a mitogen-activated protein kinase (MAPK), also known as extracellular signal-regulated kinase (ERK). We tested the hypothesis that activation of ERK (by phosphorylation to p-ERK) is necessary and/or sufficient for entrainment by measuring the ability of several drugs, light, and other perturbations to change levels of p-ERK and to induce phase shifts in the melatonin rhythm. If changes in the levels of p-ERK are sufficient for photoentrainment, then all perturbations that reduce its level must induce light-like phase shifts, and all those that increase its level must induce dark-like phase shifts. If such changes are necessary for photoentrainment, then light pulses must reduce p-ERK levels, and the duration of the light pulse, the magnitude and duration of the change in p-ERK, and the size of the phase shift must correlate. We found five perturbations that reduced p-ERK levels. Of these, two induced light-like phase shifts (PD 98059 and caffeine), one induced dark-like phase shifts (SB203580), and two did not induce phase shifts at all (U0126 and omitting a medium change). Serum increased p-ERK levels without inducing any phase shifts. Finally, light pulses did not elicit changes in p-ERK, nor was there a diurnal rhythm in p-ERK levels, nor could rapid changes in p-ERK levels have accounted for duration effects of light pulses on phase shifts. Taken together, these results argue strongly against the hypothesis that reduction (or increases) in MAPK/ERK activation is necessary or sufficient for entrainment in chick pineal cells.

Key words: MAPK; ERK; MEK inhibitor; circadian rhythms; clocks; entrainment; signal transduction; melatonin

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Received July 29, 2003; revised September 3, 2003; accepted September 3, 2003.

This article has been cited by other articles:

				M. Hasegawa and G. M. Cahill Regulation of the Circadian Oscillator in Xenopus Retinal Photoreceptors by Protein Kinases Sensitive to the Stress-activated Protein Kinase Inhibitor, SB 203580 J. Biol. Chem., May 21, 2004; 279(21): 22738 - 22746. [Abstract] [Full Text] [PDF]

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