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rdf:type |
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lifeskim:mentions |
umls-concept:C0006675,
umls-concept:C0035647,
umls-concept:C0037083,
umls-concept:C0054450,
umls-concept:C0205374,
umls-concept:C0596981,
umls-concept:C0597357,
umls-concept:C1421170,
umls-concept:C1425400,
umls-concept:C1710082,
umls-concept:C1948027
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pubmed:issue |
26
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pubmed:dateCreated |
2011-6-29
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pubmed:abstractText |
Cardiac transient receptor potential canonical (TRPC) channels are crucial upstream components of Ca(2+)/calcineurin/nuclear factor of activated T cells (NFAT) signaling, thereby controlling cardiac transcriptional programs. The linkage between TRPC-mediated Ca(2+) signals and NFAT activity is still incompletely understood. TRPC conductances may govern calcineurin activity and NFAT translocation by supplying Ca(2+) either directly through the TRPC pore into a regulatory microdomain or indirectly via promotion of voltage-dependent Ca(2+) entry. Here, we show that a point mutation in the TRPC3 selectivity filter (E630Q), which disrupts Ca(2+) permeability but preserves monovalent permeation, abrogates agonist-induced NFAT signaling in HEK293 cells as well as in murine HL-1 atrial myocytes. The E630Q mutation fully retains the ability to convert phospholipase C-linked stimuli into L-type (Ca(V)1.2) channel-mediated Ca(2+) entry in HL-1 cells, thereby generating a dihydropyridine-sensitive Ca(2+) signal that is isolated from the NFAT pathway. Prevention of PKC-dependent modulation of TRPC3 by either inhibition of cellular kinase activity or mutation of a critical phosphorylation site in TRPC3 (T573A), which disrupts targeting of calcineurin into the channel complex, converts cardiac TRPC3-mediated Ca(2+) signaling into a transcriptionally silent mode. Thus, we demonstrate a dichotomy of TRPC-mediated Ca(2+) signaling in the heart constituting two distinct pathways that are differentially linked to gene transcription. Coupling of TRPC3 activity to NFAT translocation requires microdomain Ca(2+) signaling by PKC-modified TRPC3 complexes. Our results identify TRPC3 as a pivotal signaling gateway in Ca(2+)-dependent control of cardiac gene expression.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-10381584,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-10931826,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-10964570,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-11893331,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-14736881,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-14736889,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-15199065,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-15533987,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-15845551,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-15994335,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-16460288,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-16511595,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-16873889,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-16950785,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-17082763,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-17099778,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-17129578,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-17234592,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-18193651,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-18849655,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-19289841,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-19351902,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21653882-19797170
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1091-6490
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
28
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pubmed:volume |
108
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
10556-61
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pubmed:dateRevised |
2011-9-28
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pubmed:meshHeading |
pubmed-meshheading:21653882-Animals,
pubmed-meshheading:21653882-Calcineurin,
pubmed-meshheading:21653882-Calcium,
pubmed-meshheading:21653882-Cell Line,
pubmed-meshheading:21653882-Humans,
pubmed-meshheading:21653882-Ion Transport,
pubmed-meshheading:21653882-Mice,
pubmed-meshheading:21653882-Myocardium,
pubmed-meshheading:21653882-NFATC Transcription Factors,
pubmed-meshheading:21653882-Phosphorylation,
pubmed-meshheading:21653882-Protein Kinase C,
pubmed-meshheading:21653882-Signal Transduction,
pubmed-meshheading:21653882-TRPC Cation Channels
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pubmed:year |
2011
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pubmed:articleTitle |
PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes.
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pubmed:affiliation |
Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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