Volpi M, Sha'afi R I, Epstein P M, Andrenyak D M, Feinstein M B
Proc Natl Acad Sci U S A. 1981 Feb;78(2):795-9. doi: 10.1073/pnas.78.2.795.
Local anesthetics such as dibucaine, QX572, tetracaine, and phenacaine, as well as other drugs with local anesthetic-like properties (e.g., mepacrine, propranolol, and SKF 525A) inhibit the specific calmodulin-dependent stimulation of erythrocyte Ca2+-ATPase (ATP phosphohydrolase, EC 3.6.1.3) and cyclic nucleotide phosphodiesterases (3',5'-cyclic-nucleotide 5'-nucleotidohydrolase, EC 3.1.4.17) from brain and heart. Basal activities of these enzymes in the absence of calmodulin are relatively unaffected by concentrations of local anesthetics that strongly inhibit the specific stimulation by calmodulin. Increasing calmodulin, but not Ca2+, overcomes the inhibitory action of the local anesthetics on brain phosphodiesterase. However, excess calmodulin does not fully restore activity of erythrocyte CA2+-stimulated ATPase. Although the mechanism(s) by which the local anesthetics act is unclear, they inhibit binding of 125I-labeled calmodulin to the erythrocyte membrane. Antagonism of calmodulin provides a molecular mechanism that may explain the inhibition of many Ca2+-dependent cellular processes by local anesthetics--e.g., Ca2+ transport, exocytosis, excitation-contraction coupling, non-muscle-cell motility, and aggregation.
诸如丁卡因、QX572、丁哌卡因和非那卡因等局部麻醉药，以及其他具有类似局部麻醉性质的药物（如米帕林、普萘洛尔和SKF 525A），可抑制红细胞Ca2 + -ATP酶（ATP磷酸水解酶，EC 3.6.1.3）以及来自脑和心脏的环核苷酸磷酸二酯酶（3'，5'-环核苷酸5'-核苷酸水解酶，EC 3.1.4.17）的特异性钙调蛋白依赖性刺激。在没有钙调蛋白的情况下，这些酶的基础活性相对不受强烈抑制钙调蛋白特异性刺激的局部麻醉药浓度的影响。增加钙调蛋白而非Ca2 +可克服局部麻醉药对脑磷酸二酯酶的抑制作用。然而，过量的钙调蛋白并不能完全恢复红细胞CA2 +刺激的ATP酶的活性。尽管局部麻醉药的作用机制尚不清楚，但它们可抑制125I标记的钙调蛋白与红细胞膜的结合。钙调蛋白的拮抗作用提供了一种分子机制，这可能解释了局部麻醉药对许多Ca2 +依赖性细胞过程的抑制作用，例如Ca2 +转运、胞吐作用、兴奋-收缩偶联、非肌肉细胞运动和聚集。
