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

Apr 9, 2011Neuroendocrinology

Daily and seasonal changes in a key enzyme in the rat pineal gland and its role in cell signaling

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Abstract

PDE10A expression in the pineal gland shows daily and seasonal fluctuations.

PDE10A transcript levels exhibit cyclic changes that persist in constant darkness but are inhibited by constant light.
The daily fluctuation of PDE10A mRNA is likely regulated by the suprachiasmatic nucleus, the brain's master clock.
Adrenergic agonists and dibutyryl-cAMP can increase PDE10A mRNA levels, indicating a signaling pathway involving norepinephrine and cAMP.
Inhibition of PDE10A by papaverine enhances cAMP and cGMP signaling, suggesting it downregulates these pathways.
PDE10A inhibition also increases induction of the gene responsible for melatonin production in the pineal gland.

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The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal spiny projection neurons and represents a therapeutic target for the treatment of psychotic symptoms. As reported previously [J Biol Chem 2009; 284:7606-7622], in this study PDE10A was seen to be additionally expressed in the pineal gland where the levels of PDE10A transcript display daily changes. As with the transcript, the amount of PDE10A protein was found to be under daily and seasonal regulation. The observed cyclicity in the amount of PDE10A mRNA persists under constant darkness, is blocked by constant light and is modulated by the lighting regime. It therefore appears to be driven by the master clock in the suprachiasmatic nucleus (SCN). Since adrenergic agonists and dibutyryl-cAMP induce PDE10A mRNA, the in vitro clock-dependent control of Pde10a appears to be mediated via a norepinephrine → β-adrenoceptor → cAMP/protein kinase A signaling pathway. With regard to the physiological role of PDE10A in the pineal gland, the specific PDE10A inhibitor papaverine was seen to enhance the adrenergic stimulation of the second messenger cAMP and cGMP. This indicates that PDE10A downregulates adrenergic cAMP and cGMP signaling by decreasing the half-life of both nucleotides. Consistent with its effect on cAMP, PDE10A inhibition also amplifies adrenergic induction of the cAMP-inducible gene arylalkylamine N-acetyltransferase (Aanat) which codes the rate-limiting enzyme in pineal melatonin formation. The findings of this study suggest that Pde10a expression is under circadian and seasonal regulation and plays a modulatory role in pineal signal transduction and gene expression.

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

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