Daily Rhythm in Pineal Phosphodiesterase (PDE) Activity Reflects Adrenergic/3′,5′-Cyclic Adenosine 5′-Monophosphate Induction of the PDE4B2 Variant

Section on Neuroendocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Endocrinology (Impact Factor: 4.5). 05/2007; 148(4):1475-85. DOI: 10.1210/en.2006-1420
Source: PubMed


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 (approximately 5-fold; doubling time, approximately 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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    • "PDE inhibitors are being extensively investigated for their efficacy in the treatment of a range of neurodegenerative disorders, including PD [162], affording protection in the MPTP model [200] and on BBBp [201]. PDE4 inhibitors will also increase night-time melatonin levels [202]. PDE2A inhibitors are under extensive research in the treatment of inflammatory processes [203], which as indicated above would have significance in PD and therefore in peripherally derived TRYCATs, as well as on AHr regulation. "
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    • "PDE4B mRNA demonstrates a specific circadian rhythm, with peak levels at night in the rat pineal four hours into the dark phase that progressively decline into the light phase. PDE4B2 levels are five-fold greater at night versus the day.27 As we did not measure PDE gene expression at different circadian timepoints, we cannot specifically comment on chronic antidepressant induced alterations in the circadian rhythms of PDEs in the pineal gland. "
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