Soergel D G, Gusovsky F, Yasumoto T, Daly J W
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, maryland.
J Pharmacol Exp Ther. 1990 Dec;255(3):1360-5.
In hamster insulinoma (HIT) cells, maitotoxin (MTX) induces a time-dependent and concentration-dependent release of insulin that requires the presence of extracellular calcium. The response is nearly completely blocked by cinnarizine and cadmium, but is not inhibited by the L-type calcium channel blocker nifedipine or by manganese. MTX induces 45Ca+ uptake in these cells in a dose-dependent mode, and the uptake is blocked with cinnarizine, nifedipine and cadmium, and is partially inhibited by manganese. MTX induces phosphoinositide breakdown in HIT cells, and the response is partially blocked by cadmium, but is not affected by nifedipine, cinnarizine or manganese. High concentrations of potassium ions also induce insulin release and calcium uptake in HIT cells. Both effects of potassium are blocked partially by nifedipine, cadmium and cinnarizine. High concentrations of potassium do not induce phosphoinositide breakdown in HIT cells. The results suggest that MTX-elicited release of insulin is attained by two mechanisms: 1) a nifedipine-sensitive action, which results from MTX-induced activation of L-type calcium channels, which can be mimicked with high potassium concentrations; and 2) a nifedipine-insensitive action, which may be initiated by the activation of phosphoinositide breakdown by MTX. Such an activation of phospholipase C would result in the formation of 1,4,5-inositol trisphosphate, a release of intracellular calcium and then release of insulin to the extracellular space. Cinnarizine is proposed to block both MTX-elicited mechanisms, the first by blockade of calcium channels and the second by blocking 1,4,5-inositol trisphosphate-induced release of internal calcium. Either mechanism alone appears capable of eliciting release of insulin.
在仓鼠胰岛素瘤（HIT）细胞中， maitotoxin（MTX）诱导胰岛素呈时间和浓度依赖性释放，这需要细胞外钙的存在。该反应几乎完全被桂利嗪和镉阻断，但不受L型钙通道阻滞剂硝苯地平或锰的抑制。MTX以剂量依赖性方式诱导这些细胞摄取45Ca+，并且该摄取被桂利嗪、硝苯地平和镉阻断，并且被锰部分抑制。MTX诱导HIT细胞中的磷酸肌醇分解，该反应被镉部分阻断，但不受硝苯地平、桂利嗪或锰的影响。高浓度钾离子也诱导HIT细胞释放胰岛素和摄取钙。钾的这两种作用都被硝苯地平、镉和桂利嗪部分阻断。高浓度钾不诱导HIT细胞中的磷酸肌醇分解。结果表明，MTX引发的胰岛素释放通过两种机制实现：1）硝苯地平敏感作用，这是由MTX诱导的L型钙通道激活引起的，高钾浓度可模拟该作用；2）硝苯地平不敏感作用，这可能由MTX激活磷酸肌醇分解引发。磷脂酶C的这种激活将导致1,4,5-肌醇三磷酸的形成、细胞内钙的释放，进而导致胰岛素释放到细胞外空间。有人提出桂利嗪可阻断MTX引发的两种机制，第一种是通过阻断钙通道，第二种是通过阻断1,4,5-肌醇三磷酸诱导的细胞内钙释放。单独任何一种机制似乎都能够引发胰岛素释放。
