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Section on Neuroendocrinology, Office of the Scientific Director (J.-S.K., M.J.B., P.G., D.C.K.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Department of Physiology, Faculty of Medicine (A.K.H.), University of Alberta, Edmonton, Alberta, Canada T6G 2H7; and Institute of Medical Anatomy, Panum Institute (M.M.), University of Copenhagen, 3 Blegdamsvej, 2200 Copenhagen N, Denmark
Address all correspondence and requests for reprints to: David C. Klein, Building 49, Room 6A82, National Institutes of Health, Bethesda, Maryland 20892. E-mail: kleind{at}mail.nih.gov.
The pineal gland is a photoneuroendocrine transducer that influences circadian and circannual dynamics of many physiological functions via the daily rhythm in melatonin production and release. Melatonin synthesis is stimulated at night by a photoneural system through which pineal adenylate cyclase is adrenergically activated, resulting in an elevation of cAMP. cAMP enhances melatonin synthesis through actions on several elements of the biosynthetic pathway. cAMP degradation also appears to increase at night due to an increase in phosphodiesterase (PDE) activity, which peaks in the middle of the night. Here, it was found that this nocturnal increase in PDE activity results from an increase in the abundance of PDE4B2 mRNA (
5-fold; doubling time, 2 h). The resulting level is notably higher (>6-fold) than in all other tissues examined, none of which exhibit a robust daily rhythm. The increase in PDE4B2 mRNA is followed by increases in PDE4B2 protein and PDE4 enzyme activity. Results from in vivo and in vitro studies indicate that these changes are due to activation of adrenergic receptors and a cAMP-dependent protein kinase A mechanism. Inhibition of PDE4 activity during the late phase of adrenergic stimulation enhances cAMP and melatonin levels. The evidence that PDE4B2 plays a negative feedback role in adrenergic/cAMP signaling in the pineal gland provides the first proof that cAMP control of PDE4B2 is a physiologically relevant control mechanism in cAMP signaling.
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