Wilson Lindsay S, Brandon Nicholas J
Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA, USA.
Curr Pharm Des. 2015;21(3):378-88. doi: 10.2174/1381612820666140826114744.
Cyclic AMP and cyclic GMP are essential second messengers that regulate multiple signaling pathways in virtually all cell types. Their accumulation in cells is finely regulated by cyclic nucleotide phosphodiesterases (PDEs), the only enzymes that can degrade these signaling molecules and thus provide exquisite control over intracellular signaling processes. One PDE family, PDE10A, is highly enriched in the brain and its unique expression profile in specific brain regions of interest, in particular to antipsychotic treatment, has made it an attractive therapeutic target for the treatment of schizophrenia. However, after a Phase II trial failure of a selective PDE10A inhibitor for the treatment of schizophrenia, it has encouraged the field to reexamine the role of this enzyme in the brain, and the possible CNS disorders in which PDE10A inhibition could be therapeutic. We will review the localization of PDE10A, both within the brain and the neuron and discuss how its role in regulating cAMP and cGMP accumulation modulates intracellular signaling pathways. Since this cellular signaling has best been documented in the striatum, we will focus our discussion of PDE10A in the context of disorders that affect the basal ganglia, including psychiatric disorders such as bipolar disorder and autism spectrum disorders and the movement disorders, including Parkinson's disease and Huntington's disease.
环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）是重要的第二信使，几乎在所有细胞类型中调节多种信号通路。它们在细胞内的积累受到环核苷酸磷酸二酯酶（PDEs）的精细调节，PDEs是唯一能够降解这些信号分子的酶，从而对细胞内信号转导过程进行精确控制。一个PDE家族，即PDE10A，在大脑中高度富集，其在特定感兴趣脑区的独特表达谱，特别是与抗精神病治疗相关，使其成为治疗精神分裂症的一个有吸引力的治疗靶点。然而，一种用于治疗精神分裂症的选择性PDE10A抑制剂在II期试验失败后，促使该领域重新审视这种酶在大脑中的作用，以及PDE10A抑制可能具有治疗作用的潜在中枢神经系统疾病。我们将回顾PDE10A在大脑和神经元内的定位，并讨论其在调节cAMP和cGMP积累方面的作用如何调节细胞内信号通路。由于这种细胞信号转导在纹状体中记录得最为充分，我们将在影响基底神经节的疾病背景下重点讨论PDE10A，这些疾病包括双相情感障碍和自闭症谱系障碍等精神疾病以及帕金森病和亨廷顿舞蹈病等运动障碍。
