Gilbert B A, Lim Y H, Ding J, Badwey J A, Rando R R
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Biochemistry. 1995 Mar 28;34(12):3916-20. doi: 10.1021/bi00012a007.
Farnesylcysteine derivatives can initiate or inhibit superoxide (O2-) release in neutrophils. The mechanism by which one of these derivatives, farnesyl thiotriazole (FTT), initiates O2- release in neutrophils is the subject of this paper. Treatment of guinea pig neutrophils with FTT results in the rapid release of O2- by a route shown to be independent of the chemotactic peptide N-formyl-Met-Leu-Phe (fMLP) receptor. The signal transduction pathway utilized by the chemoattractant fMLP is generally accepted as the paradigm for receptor-mediated stimulation of O2- production. Antagonists of fMLP had no effect on FTT-induced O2- release, and pretreatment of neutrophils with fMLP had no effect on the ability of FTT to trigger further O2- generation. In fact, FTT behaves like a typical protein kinase C (PKC) activator. It promotes phosphorylation of the 47-kDa subunit of the NADH oxidase complex (p47-phox) in neutrophils, and this phosphorylation is specifically blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an antagonist of PKC. FTT is also shown to activate PKC in vitro in a specific and saturable fashion. FTT is approximately equipotent with (S)-diolein, a physiologically relevant activator of this kinase. FTT represents a new, and quite novel, structure for a PKC activator. PKC activators include diglycerides and the structurally diverse tumor promoters.
法尼基半胱氨酸衍生物可引发或抑制中性粒细胞中超氧化物（O2-）的释放。本文的主题是这些衍生物之一，法尼基硫代三唑（FTT）在中性粒细胞中引发O2-释放的机制。用FTT处理豚鼠中性粒细胞会导致O2-通过一条被证明独立于趋化肽N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）受体的途径快速释放。趋化剂fMLP所利用的信号转导途径通常被认为是受体介导的O2-产生刺激的范例。fMLP拮抗剂对FTT诱导的O2-释放没有影响，用fMLP预处理中性粒细胞对FTT触发进一步O2-生成的能力也没有影响。事实上，FTT的行为类似于典型的蛋白激酶C（PKC）激活剂。它促进中性粒细胞中NADH氧化酶复合物47 kDa亚基（p47-phox）的磷酸化，而这种磷酸化被PKC拮抗剂1-（5-异喹啉磺酰基）-2-甲基哌嗪（H-7）特异性阻断。FTT还被证明在体外以特定且可饱和的方式激活PKC。FTT与（S）-二油精（这种激酶的一种生理相关激活剂）的效力大致相当。FTT代表了一种新型且相当新颖的PKC激活剂结构。PKC激活剂包括甘油二酯和结构多样的肿瘤启动子。
