Select 3′,5′-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain
Select 3′,5′-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain
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DOI：
10.1016/j.cellsig.2013.10.007
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发表时间：
2014-02-01
影响因子：
4.8
通讯作者：
Kleiman, Robin J.
中科院分区：
文献类型：
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作者：
Kelly, Michy P.;Adamowicz, Wendy;Kleiman, Robin J.
3',5'-环核苷酸磷酸二酯酶 (PDE) 是唯一已知的区分 CAMP 和 cGMP 的酶，但人们对 PDE 在整个生命周期中如何动态调节知之甚少。我们使用定量聚合酶链反应 (qPCR) 和原位杂交绘制了成年大鼠和小鼠中枢神经系统 (CNS) 中所有 21 种 PDE 亚型的 mRNA 表达图谱，以评估跨物种的保守性。我们还比较了年老（26 个月）和年轻（5 个月）Sprague-Dawley 大鼠大脑中的 PDE mRNA 和蛋白质，并在年老（9 个月）和年轻（2 个月）BALB/cJ 小鼠中重复了选定的实验。我们发现，每种 PDE 同工型在大脑中都表现出独特的表达模式，这种模式在大鼠、小鼠和人类之间高度保守。 PDE1B、PDE1C、PDE2A、PDE4A、PDE4D、PDE5A、PDE7A、PDE8A、PDE8B、PDE10A 和 PDE11A 在所检查的 4 个大脑区域（海马、皮质、纹状体和小脑）中的至少 1 个区域中显示出与年龄相关的 mRNA 表达增加或减少。相反，PDE1A、PDE3A、PDE3B、PDE4B、PDE7A、PDE7B 和 PDE9A 的 mRNA 表达不随年龄变化。老年啮齿类动物与年轻啮齿动物的海马中 PDE11A4、PDE8A3、PDE8A4/5 和 PDE1C1 蛋白表达与年龄相关的增加得到证实，纹状体中 PDE8A3 蛋白表达与年龄相关的增加也是如此。 PDE 表达的年龄相关变化似乎具有功能性后果，因为相对于年轻大鼠，老年大鼠的海马表现出 GluR1、CaMKII α 和 CaMKII β 的磷酸化显着降低，跨膜 AMPA 调节蛋白 γ 2（又名 stargazin）和 γ 8 的表达降低，以及 H3K27 三甲基化增加。有趣的是，PDE11A4、PDE8A4/5、PDE8A3 和 PDE1C1 的表达与年轻大鼠而非老年大鼠的这些功能终点相关，表明衰老不仅与 PDE 表达的变化有关，还与 PDE 区室化的变化有关。 (C) 2013 Elsevier Inc. 保留所有权利。
3',5'-cyclic nucleotide phosphodiesterases (PDEs) are the only known enzymes to compartmentalize CAMP and cGMP, yet little is known about how PDEs are dynamically regulated across the lifespan. We mapped mRNA expression of all 21 PDE isoforms in the adult rat and mouse central nervous system (CNS) using quantitative polymerase chain reaction (qPCR) and in situ hybridization to assess conservation across species. We also compared PDE mRNA and protein in the brains of old (26 months) versus young (5 months) Sprague-Dawley rats, with select experiments replicated in old (9 months) versus young (2 months) BALB/cJ mice. We show that each PDE isoform exhibits a unique expression pattern across the brain that is highly conserved between rats, mice, and humans. PDE1B, PDE1C, PDE2A, PDE4A, PDE4D, PDE5A, PDE7A, PDE8A, PDE8B, PDE10A, and PDE11A showed an age-related increase or decrease in mRNA expression in at least 1 of the 4 brain regions examined (hippocampus, cortex, striatum, and cerebellum). In contrast, mRNA expression of PDE1A, PDE3A, PDE3B, PDE4B, PDE7A, PDE7B, and PDE9A did not change with age. Age-related increases in PDE11A4, PDE8A3, PDE8A4/5, and PDE1C1 protein expression were confirmed in hippocampus of old versus young rodents, as were age-related increases in PDE8A3 protein expression in the striatum. Age-related changes in PDE expression appear to have functional consequences as, relative to young rats, the hippocampi of old rats demonstrated strikingly decreased phosphorylation of GluR1, CaMKII alpha, and CaMKII beta, decreased expression of the transmembrane AMPA regulatory proteins gamma 2 (a.k.a. stargazin) and gamma 8, and increased trimethylation of H3K27. Interestingly, expression of PDE11A4, PDE8A4/5, PDE8A3, and PDE1C1 correlate with these functional endpoints in young but not old rats, suggesting that aging is not only associated with a change in PDE expression but also a change in PDE compartmentalization. (C) 2013 Elsevier Inc. All rights reserved.