INDUCIBLE MICROGLIAL NITRIC-OXIDE SYNTHASE - A LARGE MEMBRANE POOL

MICROGLIA are the only immunocompetent cells resident in the central n ervous system which are capable of protecting the brain from infection and tumors. These resident macrophages possess a vast array of mechan isms for the destruction of bacteria and tumor cells. One of these mec hanisms involves the generation of nitric oxide which can kill cells b y inhibition of glycolysis, the TCA cycle and DNA synthesis. In this r egard, we demonstrate, for the first time, that the inducible form of nitric oxide synthase (NOS) in microglia involves both cytosolic and m embrane bound pools. Both pools of NOS were potently and stereospecifi cally inhibited by NOS inhibitors. In addition, while these pools were unaffected by Ca2+, they were partially inhibited by calmodulin antag onists. These data would suggest that inducible NOS in lipopolysacchar ide (LPS) treated microglia, constitutes two major compartments and ma y involve a novel isoform which is membrane associated. With regard to the possible physiological relevance for the membrane-bound NOS, we s peculate that this presents an efficient means of supplying nitric oxi de to the extracellular environment where it could gain rapid access t o tumors and bacteria. This would result in inhibition of cellular fun ction in these invading cells while limiting access of nitric oxide to the intracellular environment of microglia where NO could lead to dep ressed microglial function.