LYSOSPHINGOLIPIDS INHIBIT PROTEIN-KINASE-C - IMPLICATIONS FOR THE SPHINGOLIPIDOSES
LYSOSPHINGOLIPIDS INHIBIT PROTEIN-KINASE-C - IMPLICATIONS FOR THE SPHINGOLIPIDOSES
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DOI：
10.1126/science.3101176
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发表时间：
1987-02-06
期刊：
影响因子：
56.9
通讯作者：
BELL, RM
中科院分区：
文献类型：
--
作者：
HANNUN, YA;BELL, RM
在体外和人血小板中，溶血鞘脂有效且可逆地抑制蛋白激酶C活性和佛波醇二丁酸酯的结合。与磷脂酰丝氨酸和sn-1，2-二酰基甘油激活蛋白激酶C一样，抑制作用受到表面稀释。因此，在混合胶束测定中的抑制作用取决于lysosphingolipids的摩尔百分比，而不是体积浓度。溶鞘脂抑制蛋白激酶C活性的摩尔百分比与磷脂酰丝氨酸和sn-1，2-二酰基甘油激活所需的摩尔百分比相似。由于溶血鞘脂在克拉伯病、戈谢病和其他鞘脂病中蓄积，因此关于蛋白激酶C的溶血鞘脂抑制代表鞘脂蓄积与这些疾病发病机制之间缺失的功能联系的假设似乎统一了现有数据。溶血鞘脂的积累将导致对神经传递、分化、发育和增殖至关重要的信号转导机制的进行性功能障碍，并最终导致细胞死亡。
Lysosphingolipids potently and reversibly inhibited protein kinase C activity and binding of phorbol dibutyrate in vitro and in human platelets. As with activation of protein kinase C by phosphatidylserine and sn-1,2-diacylglycerol, inhibition was subject to surface dilution. Accordingly, inhibition in mixed micelle assays was dependent on the molar percentage of lysosphingolipids rather than the bulk concentration. Lysosphingolipids inhibited protein kinase C activity at molar percentages similar to those required for activation by phosphatidylserine and sn-1,2-diacylglycerol. Since lysosphingolipids accumulate in Krabbe''s disease, Gaucher''s disease, and other sphingolipidoses, the hypothesis that lysosphingolipid inhibition of protein kinase C represents the missing functional link between the accumulation of sphingolipids and the pathogenesis of these disorders appears to unify existing data. The accumulation of lysosphingolipids would cause progressive dysfunction of signal transduction mechanisms vital for neural transmission, differentiation, development, and proliferation and would eventually lead to cell death.