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Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin


In mammals, many daily cycles are driven by a central circadian clock, which is based on the cell-autonomous rhythmic expression of clock genes. It is not clear, however, how peripheral cells are able to interpret the rhythmic signals disseminated from this central oscillator. Here we show that cycling expression of the clock gene Period1 in rodent pituitary cells depends on the heterologous sensitization of the adenosine A2b receptor, which occurs through the nocturnal activation of melatonin mt1 receptors. Eliminating the impact of the neurohormone melatonin simultaneously suppresses the expression of Period1 and evokes an increase in the release of pituitary prolactin. Our findings expose a mechanism by which two convergent signals interact within a temporal dimension to establish high-amplitude, precise and robust cycles of gene expression.

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Figure 1: Rhythmic expression of mPer1 mRNA and mPER1 protein in the mouse pars tuberalis (PT) is driven by endogenous melatonin.
Figure 2: Melatonin sensitizes adenosinergic and/or cAMP-mediated expression of mPER1 in rodent PT cells.
Figure 3: Disinhibition of prolactin concentrations in the blood of melatonin mt1 receptor knockout (mt1R−/−) mice.

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We thank S. M. Reppert for help with generating the melatonin mt1R−/− mice and for the antibody to mPER1; H. Zimmermann for discussion; M. L. Eifländer, C. Illickovic, D. Kärger, I. Schneider-Hüther and S. Schüßler for technical support; and E. Colnago, M. Holub, M. Kock, S. Leslie, S. Schotten and C. Schultz for help. This work was supported by grants from the Deutsche Forschungsgemeinschaft (to H.W.K. and J.H.S.), the Paul und Ursula Klein-Stiftung and the Heinrich und Fritz Riese-Stiftung (to J.H.S.), the Biotechnology and Biological Sciences Research Council and the Medical Research Council (to M.H.H.) and the NIH (AG09975 to D.R.W.).

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Correspondence to Jörg H. Stehle.

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Supplementary Fig. 1

Mechanisms for generating rhythmic gene expression in pituitary cells. At 'night', the convergent impact of adenosine and melatonin leads to acute inhibition of the cAMP signaling pathway in cells of the hypophyseal pars tuberalis, with a simultaneous heterologous sensitization of the adenosine A2b receptor (light green). This intracellular crosstalk is active during the second half of the night, when the secretion of the neurohormone melatonin from the pineal gland is high. With the decline of the inhibitory melatonin signal at 'dawn', adenosine elicits through the sensitized adenosine A2b receptor (dark green) an increased transcription of cAMP-inducible genes through phosphorylation of the activating transcription factor CREB. At 'day', the absence of the melatonin signal results in a desenstization of the adenosine A2b receptor (yellow). As a delayed consequence of the melatonin-sensitized adenosinergic signaling pathway, the translational products of cAMP-sensitive genes, such as PER1, accumulate in pituitary cells. The thickness of arrows indicates the intensity of signaling events. AC, adenylyl cyclase; ado, adenosine; A2b, adenosine 2b receptor; cAMP, cAMP; CRE, camp-responsive element; CREB, CRE-binding protein; G, G protein; P, phosphate group; PKA, protein kinase A; mel, melatonin; mt1R, melatonin mt1 receptor. (PDF 86 kb)

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von Gall, C., Garabette, M., Kell, C. et al. Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin. Nat Neurosci 5, 234–238 (2002).

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