Brown B L, Walker S W, Tomlinson S
Clin Endocrinol (Oxf). 1985 Aug;23(2):201-18. doi: 10.1111/j.1365-2265.1985.tb00216.x.
As long ago as 1970, it was proposed that Ca2+ can act as a 'second messenger' like cAMP (Rasmussen & Nagata, 1979). The recognition that calmodulin is a major Ca2+ binding protein in non-muscle cells has prompted the suggestion that calmodulin may serve an analogous role for Ca2+ to that served by protein kinase for cAMP (Wang & Waisman, 1979), or at least to the regulatory subunit of the cyclic nucleotide-dependent kinases. It is becoming clear that calmodulin probably does play a role in stimulus secretion coupling in endocrine cells. Nevertheless, some of the experimental approaches which have led to this rather tentative conclusion do induce some doubts, as we have attempted to indicate. Many of the pharmacological agents used in the studies cited in this review are not specific in their interaction with calmodulin. For example, the phenothiazines also inhibit phospholipid-sensitive protein kinase. The introduction of more specific drugs, such as the naphthalene sulphonamides, may lead to a clearer picture of the role of calmodulin in hormone secretion. Relationships probably exist between cyclic nucleotides, calcium, calmodulin, phosphatidylinositol (PI) turnover and phospholipids in the overall control of the secretory process (see Fig. 1). There is considerable evidence that calcium is the primary internal signal initiating exocytosis of hormone from many glands. However, it appears that cyclic nucleotides can modulate the calcium signal either positively or negatively and it is possible that cAMP and calcium can separately activate secretion. The presence of both calmodulin-activated adenylate cyclase and cyclic nucleotide phosphodiesterase in the same tissue would appear to suggest either spatial or temporal control mechanisms or that (diagram; see text) the calcium requirement for calmodulin activation differs between the two enzymes. The true explanation is probably far more complex and involves perhaps as yet unknown factors that can differentially influence the activity of calmodulin itself in membranes and in cytosol. Berridge (1982) and Rasmussen (1980) give detailed accounts and review current hypotheses regarding relationships between the cyclic nucleotide and calcium second messenger systems. The various possible interrelationships of the putative messengers have been encompassed by the term 'Synarchic regulation' (Rasmussen, 1980). These concepts and the elucidation of the mechanisms by which cyclic AMP and calcium are involved in the control of secretion from particular cell types will make fascinating reading over the next few years.(ABSTRACT TRUNCATED AT 400 WORDS)
早在1970年就有人提出，钙离子可以像环磷酸腺苷（cAMP）一样充当“第二信使”（拉斯穆森和永田，1979年）。钙调蛋白是非肌肉细胞中主要的钙离子结合蛋白这一认识，促使人们提出钙调蛋白在钙离子方面可能发挥着与蛋白激酶在环磷酸腺苷方面所起作用类似的作用（王和魏斯曼，1979年），或者至少与环核苷酸依赖性激酶的调节亚基所起作用类似。越来越明显的是，钙调蛋白可能在内分泌细胞的刺激 - 分泌偶联中发挥作用。然而，正如我们试图指出的那样，一些得出这一相当初步结论的实验方法确实引发了一些疑问。本综述中引用的研究中使用的许多药理试剂在与钙调蛋白相互作用方面并不具有特异性。例如，吩噻嗪类药物也会抑制磷脂敏感蛋白激酶。引入更具特异性的药物，如萘磺酰胺类药物，可能会更清楚地了解钙调蛋白在激素分泌中的作用。在分泌过程的整体控制中，环核苷酸、钙、钙调蛋白、磷脂酰肌醇（PI）周转和磷脂之间可能存在相互关系（见图1）。有大量证据表明，钙是引发许多腺体激素胞吐作用的主要内部信号。然而，似乎环核苷酸可以对钙信号产生正向或负向调节，并且环磷酸腺苷和钙可能分别激活分泌。同一组织中同时存在钙调蛋白激活的腺苷酸环化酶和环核苷酸磷酸二酯酶，这似乎表明存在空间或时间控制机制，或者（示意图；见正文）这两种酶对钙调蛋白激活的钙需求不同。真正的解释可能要复杂得多，可能涉及一些尚未知晓的因素，这些因素可以不同程度地影响钙调蛋白在细胞膜和细胞质中的活性。贝里奇（1982年）和拉斯穆森（1980年）对环核苷酸和钙第二信使系统之间的关系进行了详细阐述并综述了当前的假说。术语“协同调节”（拉斯穆森，1980年）涵盖了假定信使的各种可能的相互关系。在接下来的几年里，这些概念以及对环磷酸腺苷和钙参与特定细胞类型分泌控制机制的阐明将会是引人入胜的读物。（摘要截取自400字）
