Kakkar R, Raju R V, Sharma R K
Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Cell Mol Life Sci. 1999 Jul;55(8-9):1164-86. doi: 10.1007/s000180050364.
Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is one of the key enzymes involved in the complex interactions between the cyclic nucleotide and Ca2+ second messenger systems. Currently, three genes encode PDE1, and alternate splicing of these genes gives rise to functionally different isozymes which exhibit distinct catalytic and regulatory properties. Some isozymes have similar kinetic and immunological properties but are differentially regulated by Ca2+ and calmodulin. These isozymes also differ in their mechanism of regulation by phosphorylation. Analysis of various regulatory reactions involving Ca2+ and cyclic adenosine monophosphate (cAMP) has revealed the importance of the time dependence of these reactions during cell activation; however, no measurement is available for the time of occurrence of specific regulatory reactions. cAMP-signalling systems provide a pivotal centre for achieving crosstalk regulation by various signalling pathways. It has been proposed that polypeptide sequences enriched in proline (P), glutamate (E), serine (S) and threonine (T), known as PEST motifs, serve as putative intramolecular signals for rapid proteolytic degradation by calpains. Calpains are Ca(2+)-dependent cysteine proteases that regulate various enzymes, transcription factors and structural proteins through limited proteolysis. Isozyme PDE1A2 has a PEST motif and acts as a substrate for m-calpain. In this paper, we have described PDE1A2 regulation by calpains and its physiological implications. cAMP is an important component of the signal transduction pathway and plays an integral role in various physiological processes such as gene transcription, various neuronal functions, cardiac muscle contraction, vascular relaxation, cell proliferation and a host of other functions. It is important to identify the cellular processes where PDE isoform(s) and cAMP response are altered. This will lead to better understanding of the pathology of disease states and development of novel therapeutics. The different PDE1 isozymes, although similar in kinetic properties, can be distinguished by various pharmacological agents. Our recent understanding of the role of PDE1 inhibitors such as ginseng, dihydropy-ridine antagonists and antiparkinsonian agents are described in this review. The exact function of PDE1 isozymes in various pathophysiological processes is not clear because most of the studies have been carried out in vitro; therefore, it is essential that further research be directed to in vivo studies.
钙/钙调蛋白依赖性环核苷酸磷酸二酯酶（PDE1）是参与环核苷酸和钙第二信使系统之间复杂相互作用的关键酶之一。目前，有三个基因编码PDE1，这些基因的可变剪接产生了功能不同的同工酶，它们具有不同的催化和调节特性。一些同工酶具有相似的动力学和免疫学特性，但受钙和钙调蛋白的调节方式不同。这些同工酶在磷酸化调节机制上也存在差异。对涉及钙和环磷酸腺苷（cAMP）的各种调节反应的分析揭示了这些反应在细胞激活过程中时间依赖性的重要性；然而，对于特定调节反应发生的时间尚无测量方法。cAMP信号系统为实现各种信号通路的串扰调节提供了一个关键中心。有人提出，富含脯氨酸（P）、谷氨酸（E）、丝氨酸（S）和苏氨酸（T）的多肽序列，即所谓的PEST基序，作为钙蛋白酶快速蛋白水解降解的推定分子内信号。钙蛋白酶是依赖钙的半胱氨酸蛋白酶，通过有限的蛋白水解作用调节各种酶、转录因子和结构蛋白。同工酶PDE1A2具有PEST基序，是m-钙蛋白酶的底物。在本文中，我们描述了钙蛋白酶对PDE1A2的调节及其生理意义。cAMP是信号转导途径的重要组成部分，在基因转录、各种神经元功能、心肌收缩、血管舒张、细胞增殖等多种生理过程中发挥着不可或缺的作用。识别PDE同工型和cAMP反应发生改变的细胞过程很重要。这将有助于更好地理解疾病状态的病理学并开发新的治疗方法。不同的PDE1同工酶虽然动力学特性相似，但可以通过各种药理试剂加以区分。本综述描述了我们最近对PDE1抑制剂如人参、二氢吡啶拮抗剂和抗帕金森病药物作用的理解。由于大多数研究是在体外进行的，PDE1同工酶在各种病理生理过程中的确切功能尚不清楚；因此，必须将进一步的研究导向体内研究。
