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dc.contributor.author
Chaudhuri, Pinaki
dc.contributor.author
Rosenbaum, Michael
dc.contributor.author
Sinharoy, Pritam
dc.contributor.author
Damron, Derek S.
dc.contributor.author
Birnbaumer, Lutz
dc.contributor.author
Graham, Linda
dc.date.available
2018-10-22T20:18:03Z
dc.date.issued
2016-02
dc.identifier.citation
Chaudhuri, Pinaki; Rosenbaum, Michael; Sinharoy, Pritam; Damron, Derek S.; Birnbaumer, Lutz; et al.; Membrane translocation of TRPC6 channels and endothelial migration are regulated by calmodulin and PI3 kinase activation; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 113; 8; 2-2016; 2110-2115
dc.identifier.issn
0027-8424
dc.identifier.uri
http://hdl.handle.net/11336/62879
dc.description.abstract
Lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical transient receptor potential 6 (TRPC6) channels leading to inhibition of endothelial cell (EC) migration in vitro and delayed EC healing of arterial injuries in vivo. The precise mechanism through which lysoPC activates TRPC6 channels is not known, but calmodulin (CaM) contributes to the regulation of TRPC channels. Using site-directed mutagenesis, cDNAs were generated in which Tyr99 or Tyr138 of CaM was replaced with Phe, generating mutant CaM, Phe99-CaM, or Phe138-CaM, respectively. In ECs transiently transfected with pcDNA3.1-myc-His-Phe99-CaM, but not in ECs transfected with pcDNA3.1-myc-His-Phe138-CaM, the lysoPC-induced TRPC6-CaM dissociation and TRPC6 externalization was disrupted. Also, the lysoPC-induced increase in intracellular calcium concentration was inhibited in ECs transiently transfected with pcDNA3.1-myc-His-Phe99-CaM. Blocking phosphorylation of CaM at Tyr99 also reduced CaM association with the p85 subunit and subsequent activation of phosphatidylinositol 3-kinase (PI3K). This prevented the increase in phosphatidylinositol (3,4,5)-Trisphosphate (PIP3) and the translocation of TRPC6 to the cell membrane and reduced the inhibition of ECmigration by lysoPC. These findings suggest that lysoPC induces CaM phosphorylation at Tyr99 by a Src family kinase and that phosphorylated CaM activates PI3K to produce PIP3, which promotes TRPC6 translocation to the cell membrane.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
National Academy of Sciences
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Endothelial
dc.subject
Calmodulin
dc.subject
Pi3 Kinase
dc.subject
Trpc6
dc.subject.classification
Otras Ciencias Biológicas
dc.subject.classification
Ciencias Biológicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.title
Membrane translocation of TRPC6 channels and endothelial migration are regulated by calmodulin and PI3 kinase activation
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-06-19T16:52:51Z
dc.journal.volume
113
dc.journal.number
8
dc.journal.pagination
2110-2115
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Washington DC
dc.description.fil
Fil: Chaudhuri, Pinaki. Cleveland Clinic; Estados Unidos
dc.description.fil
Fil: Rosenbaum, Michael. Louis Stokes Cleveland Veterans Affairs Medical Center; Estados Unidos
dc.description.fil
Fil: Sinharoy, Pritam. Kent State University; Estados Unidos
dc.description.fil
Fil: Damron, Derek S.. Kent State University; Estados Unidos
dc.description.fil
Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Graham, Linda. Cleveland Clinic; Estados Unidos
dc.journal.title
Proceedings of the National Academy of Sciences of The United States of America
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/113/8/2110
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1073/pnas.1600371113
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