Institute of Microanatomy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Neuroendocrinology. 2011;94(2):113-23. doi: 10.1159/000327138. Epub 2011 Apr 7.
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.
环核苷酸磷酸二酯酶 10A（PDE10A）在纹状体棘突投射神经元中高度表达，是治疗精神症状的治疗靶点。正如之前报道的[J Biol Chem 2009; 284:7606-7622]，在这项研究中还发现 PDE10A 在松果腺中表达，松果腺中的 PDE10A 转录本水平显示出每日变化。与转录本一样，PDE10A 蛋白的含量也受到日变化和季节变化的调节。观察到的 PDE10A mRNA 含量的周期性在持续黑暗下持续存在，被持续光照阻断，并受光照制度的调节。因此，它似乎是由视交叉上核（SCN）中的主钟驱动的。由于肾上腺素能激动剂和二丁酰环腺苷酸诱导 PDE10A mRNA，体外时钟依赖性的 Pde10a 控制似乎是通过去甲肾上腺素→β-肾上腺素受体→cAMP/蛋白激酶 A 信号通路介导的。关于 PDE10A 在松果腺中的生理作用，特异性 PDE10A 抑制剂罂粟碱被发现增强了第二信使 cAMP 和 cGMP 的肾上腺素刺激。这表明 PDE10A 通过降低两个核苷酸的半衰期来下调肾上腺素能的 cAMP 和 cGMP 信号。与对 cAMP 的作用一致，PDE10A 抑制也放大了肾上腺素对 cAMP 诱导基因芳香基烷基胺 N-乙酰转移酶（Aanat）的诱导，该基因编码松果腺褪黑素形成的限速酶。这项研究的结果表明，Pde10a 的表达受昼夜和季节调节的影响，并在松果腺信号转导和基因表达中发挥调节作用。
