Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role

Tomohisa Suzuki, Izumi Hide, Akiyo Matsubara, Chihiro Hama, Kana Harada, Kanako Miyano, Matthias Andrä, Hiroaki Matsubayashi, Norio Sakai, Shinichi Kohsaka, Kazuhide Inoue, Yoshihiro Nakata

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Abstract

Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon P2X7 receptor stimulation, for example, microglia release small amounts of TNF, which protect neurons, whereas LPS causes massive TNF release leading to neuroinflammation. Here we report that, in rat primary cultured microglia, nicotine enhances P2X7 receptor-mediated TNF release, whilst suppressing LPS-induced TNF release but without affecting TNF mRNA expression via activation of α7 nicotinic acetylcholine receptors (α7 nAChRs). In microglia, nicotine elicited a transient increase in intracellular Ca2+ levels, which was abolished by specific blockers of α7 nAChRs. However, this response was independent of extracellular Ca2+ and blocked by U73122, an inhibitor of phospholipase C (PLC), and xestospongin C, a blocker of the IP3 receptor. Repeated experiments showed that currents were not detected in nicotine-stimulated microglia. Moreover, nicotine modulation of LPS-induced TNF release was also blocked by xestospongin C. Upon LPS stimulation, inhibition of TNF release by nicotine was associated with the suppression of JNK and p38 MAP kinase activation, which regulate the post-transcriptional steps of TNF synthesis. In contrast, nicotine did not alter any MAP kinase activation, but enhanced Ca 2+ response in P2X7 receptor-activated microglia. In conclusion, microglial α7 nAChRs might drive a signaling process involving the activation of PLC and Ca release from intracellular Ca2+ stores, rather than function as conventional ion channels. This novel α7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function.

Original languageEnglish
Pages (from-to)1461-1470
Number of pages10
JournalJournal of Neuroscience Research
Volume83
Issue number8
DOIs
Publication statusPublished - Jun 2006

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

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    Suzuki, T., Hide, I., Matsubara, A., Hama, C., Harada, K., Miyano, K., Andrä, M., Matsubayashi, H., Sakai, N., Kohsaka, S., Inoue, K., & Nakata, Y. (2006). Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. Journal of Neuroscience Research, 83(8), 1461-1470. https://doi.org/10.1002/jnr.20850