COMPLEMENT FACTOR C5A AND EPIDERMAL GROWTH-FACTOR TRIGGER THE ACTIVATION OF OUTWARD POTASSIUM CURRENTS IN CULTURED MURINE MICROGLIA

Microglia, the resident macrophages of the brain, are transformed from a quiescent into an activated phenotype in a number of pathological c onditions. The signalling mechanisms which control such transformation s are not yet understood. In the present study, we have characterized fast electrophysiological responses in cultured microglia, induced by two putative signalling substances, complement 5a (C5a), a chemotactic agent for macrophages and microglia, and epidermal growth factor, the receptor of which is up-regulated during pathological conditions in t he brain. Both factors transiently activate an outwardly rectifying K conductance, while the membrane of the unstimulated microglial cell i s dominated by an inwardly rectifying K+ conductance. The C5a-stimulat ed current developed within about 20 s and decayed within a slightly s lower time course. It was activated by depolarlizing voltage steps pos itive to the resting membrane potential of about -70 mV, and neither i nactivated nor showed a delayed activation following voltage steps. Th e epidermal growth factor-stimulated current showed similar characteri stics. When G-proteins were specifically blocked, the K+ conductance c ould no longer be activated by C5a or epidermal growth factor, suggest ing that for both agonists an inhibitory G-protein is involved in the intracellular signalling cascade. We tested if the induction of the K conductance is causally linked to other C5a-induced cellular response s, like transient cytosolic Ca2+ elevation and mobility. The K+ conduc tance was not activated when a Ca2+ transient was induced by thapsigar gin, nor did a blockade of the C5a-induced K+ conductance by K+ channe l blockers affect the motility response. This implies that after activ ation of the C5a receptor and the G-protein, the K+ conductance activa tion, the Ca2+ mobilization and the motility response are governed by independent intracellular pathways, and that the K+ conductance increa se must serve other functions than the control of motility. Copyright (C) 1996 IBRO. Published by Elsevier Science Ltd.