Marone G, Columbo M, Poto S, Giugliano R, Condorelli M
Life Sci. 1986 Sep 8;39(10):911-22. doi: 10.1016/0024-3205(86)90373-5.
We investigated the possible role of calmodulin (CaM) in the control of histamine release from human basophil leukocytes using several CaM antagonists. Trifluoperazine (TFP) (10(-6)-2 X 10(-5) M), pimozide (10(-6)-1.5 X 10(-5) M), chlorpromazine (CPZ) (10(-5)-10(-4) M) and promethazine (PMZ) (2 X 10(-5)-10(-4) M) inhibited in vitro histamine secretion from human basophils induced by several immunological (antigen, anti-IgE, and formyl-L-methionyl-L-leucyl-L-phenylalanine: f-met peptide) and nonimmunological (Ca2+ ionophore A23187 and the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate: TPA) stimuli. Trifluoperazine sulfoxide (TFP-S) and chlorpromazine sulfoxide (CPZ-S), which have very low affinity to CaM, had practically no inhibitory effect on histamine release from human basophils. The inhibitory effect of TFP could be made irreversible by irradiating the cells with UV light. A sulfonamide derivative, the compound N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) (2.5 X 10(-5)-2 X 10(-4) M), which selectively binds to CaM, inhibited the release of histamine from basophils. In contrast, the chloride deficient analogue, W-5, which interacts only weakly with CaM, had practically no inhibiting effect. The IC50 for enzyme release by a series of eight CaM antagonists was closely correlated (r = 0.91; p less than 0.001) with the CaM specific binding, supporting the concept that these agents act by binding to CaM and thereby inhibiting histamine release. TFP and W-7 inhibited histamine release in the absence and in the presence of increasing concentrations of extracellular Ca2+. These results emphasize the possible role of CaM in the control of histamine secretion from human basophils.
我们使用几种钙调蛋白拮抗剂研究了钙调蛋白（CaM）在控制人嗜碱性粒细胞组胺释放中的可能作用。三氟拉嗪（TFP）（10⁻⁶ - 2×10⁻⁵ M）、匹莫齐特（10⁻⁶ - 1.5×10⁻⁵ M）、氯丙嗪（CPZ）（10⁻⁵ - 10⁻⁴ M）和异丙嗪（PMZ）（2×10⁻⁵ - 10⁻⁴ M）抑制了几种免疫性（抗原、抗IgE以及甲酰-L-蛋氨酰-L-亮氨酰-L-苯丙氨酸：f-甲硫肽）和非免疫性（钙离子载体A23187以及肿瘤促进剂12-0-十四烷酰佛波醇-13-乙酸酯：TPA）刺激诱导的人嗜碱性粒细胞体外组胺分泌。对CaM亲和力极低的三氟拉嗪亚砜（TFP-S）和氯丙嗪亚砜（CPZ-S）对人嗜碱性粒细胞组胺释放几乎没有抑制作用。用紫外线照射细胞可使TFP的抑制作用不可逆。一种磺酰胺衍生物，化合物N-(6-氨基己基)-5-氯-1-萘磺酰胺盐酸盐（W-7）（2.5×10⁻⁵ - 2×10⁻⁴ M），其选择性地与CaM结合，抑制了嗜碱性粒细胞组胺的释放。相比之下，与CaM相互作用较弱的缺氯类似物W-5几乎没有抑制作用。一系列八种CaM拮抗剂释放酶的IC50与CaM特异性结合密切相关（r = 0.91；p < 0.001），支持了这些药物通过与CaM结合从而抑制组胺释放的观点。在细胞外Ca²⁺浓度增加的情况下以及不存在该浓度增加的情况下，TFP和W-7均抑制组胺释放。这些结果强调了CaM在控制人嗜碱性粒细胞组胺分泌中的可能作用。
