Farnesylcysteine derivatives can initiate or inhibit superoxide (O2̄) release in neutrophils. The mechanism by which one of these derivatives, farnesyl thiotriazole (FTT), initiates O2̄ release in neutrophils is the subject of this paper. Treatment of guinea pig neutrophils with FTT results in the rapid release of O2̄ 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 O2̄ production. Antagonists of fMLP had no effect on FTT-induced O2̄ release, and pretreatment of neutrophils with fMLP had no effect on the ability of FTT to trigger further O2̄ 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.
|Number of pages||5|
|Publication status||Published - 1995 Sept 1|
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