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dc.contributor.author
Farmer, Louise K.
dc.contributor.author
Rollason, Ruth
dc.contributor.author
Whitcomb, Daniel J.
dc.contributor.author
Ni, Lan
dc.contributor.author
Goodliff, Alexander
dc.contributor.author
Lay, Abigail C.
dc.contributor.author
Birnbaumer, Lutz
dc.contributor.author
Heesom, Kate J.
dc.contributor.author
Xu, Shang Zhong
dc.contributor.author
Saleem, Moin A.
dc.contributor.author
Welsh, Gavin I.
dc.date.available
2020-12-15T18:20:29Z
dc.date.issued
2019-10
dc.identifier.citation
Farmer, Louise K.; Rollason, Ruth; Whitcomb, Daniel J.; Ni, Lan; Goodliff, Alexander; et al.; TRPC6 Binds to and activates calpain, independent of its channel activity, and regulates podocyte cytoskeleton, cell adhesion, and motility; Synthesis-Stuttgart; Journal of the American Society of Nephrology; 30; 10; 10-2019; 1910-1924
dc.identifier.issn
1046-6673
dc.identifier.uri
http://hdl.handle.net/11336/120497
dc.description.abstract
Background Mutations in the transient receptor potential channel 6 (TRPC6) gene are associated with an inherited form of FSGS. Despite widespread expression, patients with TRPC6 mutations do not present with any other pathologic phenotype, suggesting that this protein has a unique yet unidentified rolewithin the target cell for FSGS, the kidney podocyte. Methods We generated a stable TRPC6 knockout podocyte cell line from TRPC6 knockout mice. These cells were engineered to express wild-type TRPC6, a dominant negative TRPC6mutation, or either of two disease-causing mutations of TRPC6, G109S or K874*. We extensively characterized these cells using motility, detachment, and calpain activity assays; immunofluorescence; confocal or total internal reflection fluorescence microscopy; and western blotting. Results Compared with wild-type cells, TRPC62/2 podocytes are less motile and more adhesive, with an altered actin cytoskeleton.We found that TRPC6 binds to ERK1/2 and the actin regulatory proteins, caldesmon (a calmodulin- A nd actin-binding protein) and calpain 1 and 2 (calcium-dependent cysteine proteases that control the podocyte cytoskeleton, cell adhesion, andmotility via cleavage of paxillin, focal adhesion kinase, and talin). Knockdown or expression of the truncated K874* mutation (but not expression of the gain-of-function G019S mutation or dominant negative mutant of TRPC6) results in the mislocalization of calpain 1 and 2 and significant downregulation of calpain activity; this leads to altered podocyte cytoskeleton,motility, and adhesion-characteristics of TRPC6 2/2 podocytes. Conclusions Our data demonstrate that independent of TRPC6 channel activity, the physical interaction between TRPC6 and calpain in the podocyte is important for cell motility and detachment and demonstrates a scaffolding role of the TRPC6 protein in disease.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Synthesis-Stuttgart
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
focal segmental glomerulosclerosis
dc.subject
glomerulus
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podocyte
dc.subject
renal cell biology
dc.subject.classification
Biología Celular, Microbiología
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
TRPC6 Binds to and activates calpain, independent of its channel activity, and regulates podocyte cytoskeleton, cell adhesion, and motility
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-11-25T16:38:15Z
dc.journal.volume
30
dc.journal.number
10
dc.journal.pagination
1910-1924
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Farmer, Louise K.. Bristol Medical School; Reino Unido
dc.description.fil
Fil: Rollason, Ruth. Bristol Medical School; Reino Unido
dc.description.fil
Fil: Whitcomb, Daniel J.. Bristol Medical School; Reino Unido
dc.description.fil
Fil: Ni, Lan. Bristol Medical School; Reino Unido
dc.description.fil
Fil: Goodliff, Alexander. Bristol Medical School; Reino Unido
dc.description.fil
Fil: Lay, Abigail C.. Bristol Medical School; Reino Unido
dc.description.fil
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
dc.description.fil
Fil: Heesom, Kate J.. No especifíca;
dc.description.fil
Fil: Xu, Shang Zhong. University of Hull; Reino Unido
dc.description.fil
Fil: Saleem, Moin A.. Bristol Medical School; Reino Unido
dc.description.fil
Fil: Welsh, Gavin I.. Bristol Medical School; Reino Unido
dc.journal.title
Journal of the American Society of Nephrology
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1681/ASN.2018070729
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://jasn.asnjournals.org/content/30/10/1910
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