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 Ba2+. Outward potassium currents only slightly inactivate and can be abolished by 4-aminopyridine, quinine and charybdotoxin. An increase in the intracellular free Ca2+ concentration depresses the outward potassium current. ATP or its structural analogues stimulate two types of P2-purinoceptors on microglial cells, a ligand-activated cationic channel (P2x) which produces depolarization and a G protein coupled receptor (P2Y) which produces hyper-polarization via the opening of K+ channels. Both P2X- and P2Y-receptor stimulation may increase the intracellular Ca2+ concentration. In the former case, Ca2+ enters the cells via non-selective cationic channels. In the latter case, Ca2+ may be released from intracellular stores, owing to activation of the enzyme phospholipase C and subsequent generation of inositol 1,4,5-trisphosphate (IP3). 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 P2X-purinoceptor stimulation may be counteracted by outwardly rectifying potassium channels and by hyperpolarizing P2Y-purinoceptors in non-proliferating microglia.
Illes
P
P
Pharmakologisches Institut der Universität Leipzig, Germany.
Nörenberg
W
W
Gebicke-Haerter
P J
PJ
D000818:Animals; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism / Q000502:physiology*; D008262:Macrophage Activation / Q000502:physiology*; D017628:Microglia / Q000502:physiology*; D011983:Receptors, Purinergic / Q000187:drug effects / Q000502:physiology
D007473:Ion Channels; D011983:Receptors, Purinergic