Universität zu Köln

Hagmann, Henning, Mangold, Nicole, Rinschen, Markus M., Koenig, Tim, Kunzelmann, Karl, Schermer, Bernhard ORCID: 0000-0002-5194-9000, 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 J., 32 (1). S. 208 - 223. BETHESDA: FEDERATION AMER SOC EXP BIOL. ISSN 1530-6860

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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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hagmann, Henning UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangold, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koenig, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Kunzelmann, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED orcid.org/0000-0002-5194-9000 UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Brinkkoetter, Paul T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-204806
DOI:	10.1096/fj.201700309R
Journal or Publication Title:	Faseb J.
Volume:	32
Number:	1
Page Range:	S. 208 - 223
Date:	2018
Publisher:	FEDERATION AMER SOC EXP BIOL
Place of Publication:	BETHESDA
ISSN:	1530-6860
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FOCAL SEGMENTAL GLOMERULOSCLEROSIS; PODOCYTE INJURY; ANGIOTENSIN-II; PHOSPHOPROTEOMIC ANALYSIS; TYROSINE PHOSPHORYLATION; DIABETIC-NEPHROPATHY; CARDIAC-HYPERTROPHY; NEPHROTIC SYNDROME; CATION CHANNELS; ACTIVATION Multiple languages Biochemistry & Molecular Biology; Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20480