Source:http://linkedlifedata.com/resource/pubmed/id/16407466
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
4
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pubmed:dateCreated |
2006-3-22
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pubmed:abstractText |
3,5-Bis(trifluoromethyl)pyrazole derivative (BTP2) or N-[4-3, 5-bis(trifluromethyl)pyrazol-1-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (YM-58483) is an immunosuppressive compound that potently inhibits both Ca2+ influx and interleukin-2 (IL-2) production in lymphocytes. We report here that BTP2 dosedependently enhances transient receptor potential melastatin 4 (TRPM4), a Ca2+-activated nonselective (CAN) cation channel that decreases Ca2+ influx by depolarizing lymphocytes. The effect of BTP2 on TRPM4 occurs at low nanomolar concentrations and is highly specific, because other ion channels in T lymphocytes are not significantly affected, and the major Ca2+ influx pathway in lymphocytes, ICRAC, is blocked only at 100-fold higher concentrations. The efficacy of BTP2 in blocking IL-2 production is reduced approximately 100-fold when preventing TRPM4-mediated membrane depolarization, suggesting that the BTP2-mediated facilitation of TRPM4 channels represents the major mechanism for its immunosuppressive effect. Our results demonstrate that TRPM4 channels represent a previously unrecognized key element in lymphocyte Ca2+ signaling and that their facilitation by BTP2 supports cell membrane depolarization, which reduces the driving force for Ca2+ entry and ultimately causes the potent suppression of cytokine release.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/4-methyl-4'-(3,5-bis(trifluoromethyl...,
http://linkedlifedata.com/resource/pubmed/chemical/Anilides,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-2,
http://linkedlifedata.com/resource/pubmed/chemical/TRPM Cation Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Thiadiazoles
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0026-895X
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pubmed:author |
pubmed-author:BeckAndreasA,
pubmed-author:ChengHenriqueH,
pubmed-author:FleigAndreaA,
pubmed-author:IshikawaJunJ,
pubmed-author:KinetJean-PierreJP,
pubmed-author:KubotaHirokazuH,
pubmed-author:LaunayPierreP,
pubmed-author:PennerReinholdR,
pubmed-author:TakezawaRyuichiR,
pubmed-author:YamadaToshimitsuT
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pubmed:issnType |
Print
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pubmed:volume |
69
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1413-20
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:16407466-Anilides,
pubmed-meshheading:16407466-Calcium,
pubmed-meshheading:16407466-Cell Line,
pubmed-meshheading:16407466-Humans,
pubmed-meshheading:16407466-Interleukin-2,
pubmed-meshheading:16407466-Ion Transport,
pubmed-meshheading:16407466-Jurkat Cells,
pubmed-meshheading:16407466-Lymphocytes,
pubmed-meshheading:16407466-TRPM Cation Channels,
pubmed-meshheading:16407466-Thiadiazoles
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pubmed:year |
2006
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pubmed:articleTitle |
A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating transient receptor potential melastatin 4 channel activity.
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pubmed:affiliation |
Laboratory of Cell and Molecular Signalling, Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., UHT 8, Honolulu, HI 96813, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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