Weiss B
Adv Cyclic Nucleotide Res. 1975;5:195-211.
The brain as well as other mammalian tissues contains several different forms of cyclic nucleotide phosphodiesterase separable by polyacrylamide gel electrophoresis. Each tissue and each individual type of cell has its own distinctive pattern and ratio of these multiple forms of phosphodiesterase. The different forms have several distinguishing properties and characteristics, and their activities may be differentially regulated both acutely and chronically. The enzyme forms have different stabilities, kinetic properties, substrate specificities, and sensitivities to an endogenous activator and to several inhibitors of phosphodiesterase. The phosphodiesterase inhibitors studied not only inhibit the different forms of phosphodiesterase to different degrees but apparently do so by different mechanisms. Thus whereas theophylline, cyclic GMP, and low concentrations of papaverine inhibit the phosphodiesterases by competing with the substrate (cyclic AMP), trifluoperazine apparently inhibits phosphodiesterase by interfering with the phosphodiesterase activator. This confers a great deal of specificity to this drug, since only one form of phosphodiesterase is markedly activated by the activator. Chronically, a specific form of phosphodiesterase appears to be inducible. This induction is probably controlled by the intracellular cyclic AMP concentration. The phosphodiesterase activator also appears to be regulatable, the age of the animal being one of the factors controlling its activity. Finally, since different types of cells have different relative amounts of the phosphodiesterases and since these forms of the enzyme can be differentially inhibited by drugs, it may be possible to develop drugs which will selectively increase the cyclic AMP concentration in discrete cell types. Evidence that cyclic AMP is involved in certain disease states suggests further that by selectively altering the concentration of cyclic AMP in these cells, one might be able to alter the course of the disease.
大脑以及其他哺乳动物组织含有几种不同形式的环核苷酸磷酸二酯酶，可通过聚丙烯酰胺凝胶电泳分离。每种组织和每种细胞类型都有其独特的这些多种形式磷酸二酯酶的模式和比例。不同形式具有若干独特的性质和特征，其活性可能在急性和慢性方面受到不同的调节。这些酶形式具有不同的稳定性、动力学性质、底物特异性以及对内源性激活剂和几种磷酸二酯酶抑制剂的敏感性。所研究的磷酸二酯酶抑制剂不仅对不同形式的磷酸二酯酶有不同程度的抑制作用，而且显然是通过不同的机制。因此，茶碱、环鸟苷酸和低浓度的罂粟碱通过与底物（环磷酸腺苷）竞争来抑制磷酸二酯酶，而三氟拉嗪显然是通过干扰磷酸二酯酶激活剂来抑制磷酸二酯酶。这赋予了这种药物很大的特异性，因为只有一种形式的磷酸二酯酶被激活剂显著激活。长期来看，一种特定形式的磷酸二酯酶似乎是可诱导的。这种诱导可能受细胞内环磷酸腺苷浓度的控制。磷酸二酯酶激活剂似乎也是可调节的，动物的年龄是控制其活性的因素之一。最后，由于不同类型的细胞具有不同相对量的磷酸二酯酶，并且由于这些酶形式可被药物不同程度地抑制，有可能开发出能选择性增加特定细胞类型中环磷酸腺苷浓度的药物。环磷酸腺苷参与某些疾病状态的证据进一步表明，通过选择性改变这些细胞中环磷酸腺苷的浓度，可能能够改变疾病的进程。
