Molecular mechanisms of microglial activation. B. Voltage- and purinoceptor-operated channels in microglia

Cultured, proliferating microglial cells can be further activated by lipopolysaccharide (LPS) and, thereby, turned into a non-proliferating state. While proliferating cells exhibit only inwardly rectifying potassium channels, non-proliferating cells express, in addition, outwardly rectifying potassium channels. The characteristics of the two channel populations are markedly different. Inward potassium currents inactivate and can be abolished by extracellular Cs + and Ba 2+ . Outward potassium currents only slightly inactivate and can be abolished by 4-aminopyridine, quinine and charybdotoxin. An increase in the intracellular free Ca 2+ concentration depresses the outward potassium current. ATP or its structural analogues stimulate two types of P 2 -purinoceptors on microglial cells, a ligand-activated cationic channel (P 2x ) which produces depolarization and a G protein coupled receptor (P 2γ ) which produces hyper-polarization via the opening of K + channels. Both P 2x- and P 2γ -receptor stimulation may increase the intracellular Ca 2+ concentration. In the former case, Ca 2+ enters the cells via non-selective cationic channels. In the latter case, Ca 2+ may be released from intracellular stores, owing to activation of the enzyme phospholipase C and subsequent generation of inositol 1,4,5-trisphosphate (IP 3 ). It is assumed that neuronal damage leads to efflux of ATP into the extracellular space with subsequent activation of microglia. ATP-induced excessive depolarizations by P 2x -purinoceptor stimulation may be counteracted by outwardly rectifying potassium channels and by hyperpolarizing P 2γ -purinoceptors in non-proliferating microglia.