Wennogle Lawrence P, Hoxie Helen, Peng Youyi, Hendrick Joseph P
Alexandria Center for Life Science, Intra-Cellular Therapies, Inc., New York, 10016, NY, USA.
Rutgers University, 7 College Ave, New Brunswick, NJ, 08901, USA.
Adv Neurobiol. 2017;17:349-384. doi: 10.1007/978-3-319-58811-7_13.
The focus of this chapter is on the cyclic nucleotide phosphodiesterase 1 (PDE1) family. PDE1 is one member of the 11 PDE families (PDE 1-11). It is the only phosphodiesterase family that is calcium/calmodulin activated. As a result, whereas other families of PDEs 2-11 play a dominant role controlling basal levels of cyclic nucleotides, PDE1 is involved when intra-cellular calcium levels are elevated and, thus, has an "on demand" or activity-dependent involvement in the control of cyclic nucleotides in excitatory cells including neurons, cardiomyocytes and smooth muscle. As a Class 1 phosphodiesterase, PDE1 hydrolyzes the 3' bond of 3'-5'-cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Here, we review evidence for this family of enzymes as drug targets for development of therapies aimed to address disorders of the central nervous system (CNS) and of degenerative diseases. The chapter includes sections on the potential for cognitive enhancement in mental disorders, as well as a review of PDE1 enzyme structure, enzymology, tissue distribution, genomics, inhibitors, pharmacology, clinical trials, and therapeutic indications. Information is taken from public databases. A number of excellent reviews of the phosphodiesterase family have been written as well as reviews of the PDE1 family. References cited here are not comprehensive, rather pointing to major reviews and key publications.
本章的重点是环核苷酸磷酸二酯酶1（PDE1）家族。PDE1是11个磷酸二酯酶家族（PDE 1 - 11）中的一员。它是唯一受钙/钙调蛋白激活的磷酸二酯酶家族。因此，虽然其他PDEs 2 - 11家族在控制环核苷酸的基础水平方面起主导作用，但当细胞内钙水平升高时，PDE1会参与其中，从而在包括神经元、心肌细胞和平滑肌在内的兴奋性细胞中环核苷酸的控制中发挥“按需”或活性依赖性作用。作为1类磷酸二酯酶，PDE1水解3'-5'-环核苷酸、环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）的3'键。在此，我们综述了将这类酶作为药物靶点以开发针对中枢神经系统（CNS）疾病和退行性疾病治疗方法的证据。本章包括关于精神障碍中认知增强潜力的部分，以及对PDE1酶结构、酶学、组织分布、基因组学、抑制剂、药理学、临床试验和治疗适应症的综述。信息取自公共数据库。已经有许多关于磷酸二酯酶家族以及PDE1家族的优秀综述。这里引用的参考文献并不全面，而是指向主要综述和关键出版物。
