Kelly Michy P
Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, 6439 Garners Ferry Road, VA Bldg 1, 3rd Floor, D-12, Columbia, SC, 29209, USA.
Adv Neurobiol. 2017;17:201-230. doi: 10.1007/978-3-319-58811-7_8.
The most recently discovered 3',5'-cyclic nucleotide phosphodiesterase family is the Phosphodiesterase 11 (PDE11) family, which is encoded by a single gene PDE11A. PDE11A is a dual-specific PDE, breaking down both cAMP and cGMP. There are four PDE11A splice variants (PDE11A1-4) with distinct tissue expression profiles and unique N-terminal regulatory regions, suggesting that each isoform could be individually targeted with a small molecule or biologic. PDE11A4 is the PDE11A isoform expressed in brain and is found in the hippocampal formation of humans and rodents. Studies in rodents show that PDE11A4 mRNA expression in brain is, in fact, restricted to the hippocampal formation (CA1, possibly CA2, subiculum, and the adjacently connected amygdalohippocampal area). Within the hippocampal formation of rodents, PDE11A4 protein is expressed in neurons but not astrocytes, with a distribution across nuclear, cytoplasmic, and membrane compartments. This subcellular localization of PDE11A4 is altered in response to social experience in mouse, and in vitro studies show the compartmentalization of PDE11A4 is controlled, at least in part, by homodimerization and N-terminal phosphorylation. PDE11A4 expression dramatically increases in the hippocampus with age in the rodent hippocampus, from early postnatal life to late aging, suggesting PDE11A4 function may evolve across the lifespan. Interestingly, PDE11A4 protein shows a three to tenfold enrichment in the rodent ventral hippocampal formation (VHIPP; a.k.a. anterior in primates) versus dorsal hippocampal formation (DHIPP). Consistent with this enrichment in VHIPP, studies in knockout mice show that PDE11A regulates the formation of social memories and the stabilization of mood and is a critical mechanism by which social experience feeds back to modify the brain and subsequent social behaviors. PDE11A4 likely controls behavior by regulating hippocampal glutamatergic, oxytocin, and cytokine signaling, as well as protein translation. Given its unique tissue distribution and relatively selective effects on behavior, PDE11A may represent a novel therapeutic target for neuropsychiatric, neurodevelopmental, or age-related disorders. Therapeutically targeting PDE11A4 may be a way to selectively restore aberrant cyclic nucleotide signaling in the hippocampal formation while leaving the rest of the brain and periphery untouched, thus, relieving deficits while avoiding unwanted side effects.
最近发现的3',5'-环核苷酸磷酸二酯酶家族是磷酸二酯酶11（PDE11）家族，它由单个基因PDE11A编码。PDE11A是一种双特异性磷酸二酯酶，可分解cAMP和cGMP。有四种PDE11A剪接变体（PDE11A1 - 4），具有不同的组织表达谱和独特的N端调节区域，这表明每种同工型都可以用小分子或生物制剂单独靶向。PDE11A4是在大脑中表达的PDE11A同工型，存在于人类和啮齿动物的海马结构中。对啮齿动物的研究表明，实际上大脑中PDE11A4 mRNA的表达仅限于海马结构（CA1，可能还有CA2、下托以及相邻连接的杏仁核海马区）。在啮齿动物的海马结构中，PDE11A4蛋白在神经元中表达，而在星形胶质细胞中不表达，分布于细胞核、细胞质和膜区室。PDE11A4的这种亚细胞定位在小鼠中会因社会经验而改变，体外研究表明，PDE11A4的区室化至少部分受同二聚化和N端磷酸化控制。从出生后早期到衰老后期，啮齿动物海马体中PDE11A4的表达随年龄在海马体中显著增加，这表明PDE11A4的功能可能在整个生命周期中发生演变。有趣的是，与背侧海马结构（DHIPP）相比，PDE11A4蛋白在啮齿动物腹侧海马结构（VHIPP；在灵长类动物中也称为前部）中富集三到十倍。与VHIPP中的这种富集一致，对基因敲除小鼠的研究表明，PDE11A调节社会记忆的形成和情绪的稳定，是社会经验反馈以改变大脑和随后社会行为的关键机制。PDE11A4可能通过调节海马谷氨酸能、催产素和细胞因子信号以及蛋白质翻译来控制行为。鉴于其独特的组织分布和对行为的相对选择性影响，PDE11A可能代表神经精神、神经发育或与年龄相关疾病的新型治疗靶点。治疗性靶向PDE11A4可能是一种选择性恢复海马结构中异常环核苷酸信号传导的方法，同时不影响大脑其他部分和外周，从而缓解缺陷同时避免不必要的副作用。
