Signaling and neuroprotective function of α7 nicotinic acetylcholine receptors in microglia

Microglia, the brain resident macrophage-like cells, play a critical role in both neuroprotection and neurodegeneration. We previously reported that the activation of P2X(7) receptors by ATP in microglia causes the release of small amounts of tumor necrosis factor (TNF), which protects neurons, while the activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) produces massive TNF leading to inflammation and neuronal destruction. alpha 7 nicotinic acetylcholine receptors (alpha 7 nAChRs) are known as ligand-gated ion channels expressed mainly in neurons. We have found that rat primary cultured microglia express 0 nAChRs which might drive a signaling process involving the activation of PLC and Ca2+ release from IP3-sensitive stores, rather than operating as ion channels. Furthermore, nicotine enhanced P2X(7) receptor-mediated protective TNF release, but suppressed LPS-induced toxic TNF release from microglia through the activation of a7 nAChRs. Because the overactivation of microglia is implicated in the pathogenesis of brain inflammatory diseases including ischemia and neurodegenerative diseases, alpha 7 nAChRs may be a potential therapeutic target which suppresses the inflammatory state and promotes the neuroprotective function of microglia.