The study for new regulating mechanism of neuronal nicotinic acetylcholine receptor and the development of new therapeutics for psycho-neurological disorders
| Project/Area Number |
18590234
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Hiroshima Institute of Technology |
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Principal Investigator |
MATSUBAYASHI Hiroaki Hiroshima Institute of Technology, Faculty of applied information science, Full Professor (60165850)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,930,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | nicotinic receptor / microglia / PLC activity / ion channel / RT-PCR / 細胞内カルシウム / PKC |
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| Research Abstract |
The alpha7 type of nicotinic acetylcholine receptors (nAChRs) are homopentameric ion channels with high Ca^<2+> permeability. Although the nAChRs were thought to be expressed mainly in neuronal cells, recent evidence indicates that these receptors also function in some non-neuronal cell types. I have found that in rat primary culture microglia, nicotine elicits a transient increase in intracellular Ca^<2+> levels, which is abolished by specific blockers of nAChRs, methyllycaconitine and alpha-bungarotoxin. However, this response is not affected by the absence of extracellular Ca^<2+> and is blocked by U73122, an inhibitor of phospholipase C (PLC), and xestospongin C, a blocker of the IP_3 receptor. Extensive electrophysiological measurements failed to reveal any nicotine-induced currents in microglia. These results suggest that microglial nAChRs drive a signaling process involving the activation of PLC and Ca^<2+> release from 1P_3-sensitive stores, rather than operating as ion channels. Furthermore, the activation of nAChRs enhanced BzATP-stimulated TNF release (P2X_7 receptor activation), but suppressed lipopolysaccahride (LPS)-induced TNF release (Toll-like receptor 4 activation), without affecting the expression of TNF mRNA. In LPS-stimulated microglia, the decreased TNF release induced by nicotine was associated with the suppression of the activation of JNK and p38 MAP kinases, which regulate the post-transcriptional steps of TNF synthesis. On the other hand, nicotine had no effect on the activation of either MAP kinase induced by BzATP, but enhanced BzATP-elicited Ca^<2+> influx. It still remains to study why the microglial nAChRs have no ion channel activities, although their cDNA sequences are as same as those of neurons.
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Report
(3 results)
Research Products
(5 results)
