Hagmann, Henning and Mangold, Nicole and Rinschen, Markus M. and Koenig, Tim and Kunzelmann, Karl and Schermer, Bernhard and Benzing, Thomas and Brinkkoetter, Paul T. (2018) Proline-dependent and basophilic kinases phosphorylate human TRPC6 at serine 14 to control channel activity through increased membrane expression. FASEB JOURNAL, 32 (1). 208-+. ISSN 0892-6638, 1530-6860
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FOCAL SEGMENTAL GLOMERULOSCLEROSIS; PODOCYTE INJURY; ANGIOTENSIN-II; PHOSPHOPROTEOMIC ANALYSIS; TYROSINE PHOSPHORYLATION; DIABETIC-NEPHROPATHY; CARDIAC-HYPERTROPHY; NEPHROTIC SYNDROME; CATION CHANNELS; ACTIVATION; MAPK; cyclin-dependent kinase 5; proteinuria; podocyte; glomerular disease |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2020 05:38 |
| Last Modified: | 23 Mar 2020 05:38 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15482 |
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