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

Abstract

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.

Night/Day Changes in Pineal Expression of >600 Genes

“…Such a relationship is seen in the pineal gland in the case of Mat2a, Slc15a1, Pde4b, and Fcer1a (22,23,75,76); in these cases, the transcripts and encoded proteins appear to have similar stability. However, the daily changes in gene expression in other cases may be only slowly translated into changes in proteins over a period of days or weeks, not hours, thereby providing an integrated measure of prior levels of activity, i.e.…”

“…Accordingly, the complete annotation of the rat genome will further expand the number of genes that are expressed differentially on a 24-h basis in the pineal gland, as will more frequent time sampling. Furthermore, the precise nature of the transcripts encoded by genes cannot be reliably predicted from the results of microarray studies, because the microarray probes are based on 3Ј sequence; this may not detect differential splicing and/or the actions of alternative promoters, which can markedly alter the expressed transcript, as seen with Crem, Slc15a1, Atp7b, and Pde4b (21,23,24,74).…”

Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease

“…PDE4 specific enzymatic activity was determined using PDE4 assay kit (FabGennix International, Frisco, TX) as described previously (13). Briefly, cells were lysed after treatment using SolObuffer (FabGennix International), and 25 g protein was used per assay.…”

Phosphodiesterase 10A in the Rat Pineal Gland: Localization, Daily and Seasonal Regulation of Expression and Influence on Signal Transduction

“…In the rat pineal gland, PDE activities for cAMP and cGMP have been shown to display daily rhythms with peak values at night [15,16]. Circadian regulation of the cAMP-specific PDE4B partly or fully accounts for the daily rhythm in the pineal PDE activity for hydrolysis of cAMP [17], but does not explain the daily alterations in pineal PDE activity for degradation of cGMP. Accordingly, further types of PDE other than PDE4B presumably form part of the molecular basis producing diurnal changes in PDE activity.…”