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FASEB J. 2018 Jan;32(1):208-219. doi: 10.1096/fj.201700309R. Epub 2017 Sep 6.

Proline-dependent and basophilic kinases phosphorylate human TRPC6 at serine 14 to control channel activity through increased membrane expression.

Author information

1
Department II of Internal Medicine, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
2
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
3
Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
4
Institute for Genetics Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; and.
5
Department of Physiology, University Regensburg, Regensburg, Germany.
6
Department II of Internal Medicine, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; paul.brinkkoetter@uk-koeln.de.

Abstract

Signaling via the transient receptor potential (TRP) ion channel C6 plays a pivotal role in hereditary and sporadic glomerular kidney disease. Several studies have identified gain-of-function mutations of TRPC6 and report induced expression and enhanced channel activity of TRPC6 in association with glomerular diseases. Interfering with TRPC6 activity may open novel therapeutic pathways. TRPC6 channel activity is controlled by protein expression and stability as well as intracellular trafficking. Identification of regulatory phosphorylation sites in TRPC6 and corresponding protein kinases is essential to understand the regulation of TRPC6 activity and may result in future therapeutic strategies. In this study, an unbiased phosphoproteomic screen of human TRPC6 identified several novel serine phosphorylation sites. The phosphorylation site at serine 14 of TRPC6 is embedded in a basophilic kinase motif that is highly conserved across species. We confirmed serine 14 as a target of MAPKs and proline-directed kinases like cyclin-dependent kinase 5 (Cdk5) in cell-based as well as in vitro kinase assays and quantitative phosphoproteomic analysis of TRPC6. Phosphorylation of TRPC6 at serine 14 enhances channel conductance by boosting membrane expression of TRPC6, whereas protein stability and multimerization of TRPC6 are not altered, making serine 14 phosphorylation a potential drug target to interfere with TRPC6 channel activity.-Hagmann, H., Mangold, N., Rinschen, M. M., Koenig, T., Kunzelmann, K., Schermer, B., Benzing, T., Brinkkoetter, P. T. Proline-dependent and basophilic kinases phosphorylate human TRPC6 at serine 14 to control channel activity through increased membrane expression.

KEYWORDS:

MAPK; cyclin-dependent kinase 5; glomerular disease; podocyte; proteinuria

PMID:
28877958
PMCID:
PMC5731127
[Available on 2019-01-01]
DOI:
10.1096/fj.201700309R

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