HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/C558    most recent 00077.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schlöndorff, J. Articles by Pollak, M. R. Search for Related Content PubMed PubMed Citation Articles by Schlöndorff, J. Articles by Pollak, M. R.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription

¹Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ²Hydra Biosciences, Cambridge, Massachusetts; and ³Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts

Submitted 11 February 2008 ; accepted in final form 7 January 2009

Mutations in the canonical transient receptor potential channel TRPC6 lead to an autosomal dominant form of human kidney disease characterized histologically by focal and segmental glomerulosclerosis. Several of these mutations enhance the amplitude and duration of the channel current. However, the effect of these mutations on the downstream target of TRPC6, the nuclear factor of activated T cell (NFAT) transcription factors, has not been previously examined. Here we demonstrate that all three TRPC6 mutations previously shown to enhance channel activity lead to enhanced basal NFAT-mediated transcription in several cell lines, including cultured podocytes. These effects are dependent on channel activity and are dominant when mutants are coexpressed with wild-type TRPC6. While TRPC6 mutants do not demonstrate an increase in basal channel currents, a subset of cells expressing the R895C and E897K mutants have elevated basal calcium levels as measured by Fura-2 imaging. Activation of NFAT by TRPC6 mutants is blocked by inhibitors of calcineurin, calmodulin-dependent kinase II, and phosphatidylinositol 3-kinase. PP2 partially inhibits NFAT activation by mutant TRPC6 independently of Src, Yes, or Fyn. Differences in channel glycosylation and surface expression do not explain the ability of mutants to enhance NFAT activation. Taken together, these results identify the activation of the calcineurin-NFAT pathway as a potential mediator of focal segmental glomerulosclerosis.

calcium; calcineurin; phosphatidylinositol 3-kinase; podocyte; canonical transient receptor potential channel

This article has been cited by other articles:

				E. Machuca, G. Benoit, and C. Antignac Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology Hum. Mol. Genet., October 15, 2009; 18(R2): R185 - R194. [Abstract] [Full Text] [PDF]