Down‐regulation of the Pineal Response to Adrenergic Stimulation Mediated by cAMP Induction of Phosphodiesterase 4B2

Abstract

As a photoneuroendocrine transducer, the pineal gland influences circadian and circannual features of a broad range of physiological functions. These effects are mediated by the nocturnal increase in circulating melatonin, the pineal hormone. Melatonin synthesis is stimulated by NE acting through cAMP. In the study presented here, it was found that NE also induces the expression a member of the cyclic nucleotide phosphodiesterase family, PDE4B2. Pineal PDE4B2 mRNA levels increase > 6-fold at night to levels which are > 6 higher than those in other tissues. The increase in PDE4B2 mRNA is associated with an increase in PDE4B2 protein and enzyme activity. In vitro studies indicate that pineal PDE4B2 mRNA, protein and activity levels are increased via activation of adrenergic receptors. In addition, PDE4B2 mRNA is elevated by cAMP protagonists; and, NE-induced elevation of PDE4B2 mRNA is blocked by inhibition of PKA. These findings indicate that NE-induced PDE4B2 gene expression is regulated by an adrenergic/cAMP/PKA mechanism. Consistent with the time course of the increase in PDE4 activity, it was also found that selective PDE4 inhibition with rolipram had negligible effects shortly after the initiation of adrenergic stimulation and marked effects four to eight hours later. These findings establish that the NE-dependent induction of PDE4B2 is part of a programmed negative feedback response which attenuates cAMP levels. Accordingly, PDE4B2 appears to contribute to the interval timing function of the pineal gland by controlling the dynamics of the time course of the cAMP response.