PHARMACOLOGICAL REGULATION OF CALMODULIN *
PHARMACOLOGICAL REGULATION OF CALMODULIN *
复制标题
钙调蛋白的药理学调节 *
DOI：
10.1111/j.1749-6632.1980.tb29621.x
复制
发表时间：
1980
影响因子：
5.2
通讯作者：
T. Wallace
中科院分区：
文献类型：
--
作者：
B. Weiss;W. Prozialeck;M. Cimino;Mary Sellinger Barnette;T. Wallace
许多精神药物，特别是吩噻嗪类和相关的抗精神病化合物，抑制多种钙调蛋白依赖性酶。这些化合物抑制钙调蛋白活性的机制是通过与该蛋白质的选择性钙依赖性结合。除了某些立体异构体之外，临床上有效的抗精神病药物化合物显示出与钙调蛋白的最大程度的结合。其他类别的药物，包括胺能激动剂和拮抗剂，以及非特异性中枢神经系统抑制剂和兴奋剂，显示很少或没有结合钙调蛋白。事实上，抗精神病药物与钙调蛋白结合的特异性提示了基于其与钙调蛋白的选择性结合来筛选新的和临床上更有效的抗精神病药物的可能性。在动物中产生行为效应的某些神经肽也被发现抑制钙调蛋白的活性，这表明可能存在与钙调蛋白相互作用的内源性精神病原或抗精神病肽。虽然在普通条件下，抗精神病药与钙调蛋白的结合是可逆的，但吩噻嗪类抗精神病药与钙调蛋白的结合可以通过紫外线照射的光化学方法或通过过氧化氢-过氧化物酶系统的酶促方法变得不可逆。这种标记技术应该被证明是一个有用的工具，研究钙调素的本地化和营业额。这些结果表明，几种不同的抗精神病药物的生化作用可以解释一个共同的机制，即，通过它们的结合和抑制钙调蛋白，并提高钙调蛋白可能作为某些抗精神病药物的细胞受体之一的可能性。然而，在我们能够以任何程度的确定性声明这些体外生化发现可以解释抗精神病药物的药理学和临床作用之前，必须完成进一步的研究。
A number of psychotropic drugs, particularly the phenothiazines and related antipsychotic compounds, inhibit a variety of calmodulin-dependent enzymes. The mechanism by which these compounds inhibit the activity of calmodulin is through a selective calcium-dependent binding to this protein. With the notable exception of certain stereoisomers, compounds that are clinically effective antipsychotic agents showed the greatest degree of binding to calmodulin. Other classes of pharmacological agents, including aminergic agonists and antagonists, and nonspecific central nervous system depressants and stimulants, showed little or no binding to calmodulin. In fact, the specificity with which antipsychotic drugs bind to calmodulin suggests the possibility of screening for new and clinically more effective antipsychotic agents based on their selective binding to calmodulin. Certain neuropeptides that produce behavioral effects in animals also were found to inhibit the activity of calmodulin, suggesting that there may be endogenous psychotogens or antipsychotic peptides that interact with calmodulin. Although under ordinary conditions the binding of antipsychotics to calmodulin is reversible, the binding of phenothiazine antipsychotics to calmodulin can be made irreversible either photochemically by ultraviolet irradiation, or enzymatically by a hydrogen peroxide-peroxidase system. Such a labeling technique should prove to be a useful tool to study the localization and turnover of calmodulin. These results indicate that several of the diverse biochemical actions of antipsychotic agents can be explained by a common mechanism, namely, by their binding to and inhibition of calmodulin, and raise the possibility that calmodulin may serve as one of the cellular receptors for certain antipsychotic compounds. However, further studies must be completed before we can state with any degree of certainty that these in vitro biochemical findings can explain the pharmacological and clinical actions of the antipsychotics.