title: Leucine-Rich Repeat Kinase 2 (Lrrk2)-Sensitive Na+/K+ATPase Activity in Dendritic Cells.
abstract: Leucine-rich repeat kinase 2 (Lrrk2) has been implicated in the pathophysiology of Parkinson's disease. Lrrk2 is expressed in diverse cells including neurons and dendritic cells (DCs). In DCs Lrrk2 was shown to up-regulate Na+/Ca2+-exchanger activity. The elimination of Ca2+by Na+/Ca2+-exchangers requires maintenance of the Na+gradient by the Na+/K+-ATPase. The present study thus explored whether Lrrk2 impacts on Na+/K+-ATPase expression and function. To this end DCs were isolated from gene-targeted mice lacking Lrrk2 (Lrrk2-/-) and their wild-type littermates (Lrrk2+/+). Na+/K+-ATPase activity was estimated from K+induced, ouabain sensitive, current determined by whole cell patch clamp. Na+/K+-ATPase α1 subunit transcript and protein levels were determined by RT-qPCR and flow cytometry. As a result, the K+induced current was significantly smaller in Lrrk2-/-than in Lrrk2+/+DCs and was completely abolished by ouabain (100 μM) in both genotypes. The K+induced, ouabain sensitive, current in Lrrk2+/+DCs was significantly blunted by Lrrk2 inhibitor GSK2578215A (1 μM, 24 hours). The Na+/K+-ATPase α1 subunit transcript and protein levels were significantly lower in Lrrk2-/-than in Lrrk2+/+DCs and significantly decreased by Lrrk2 inhibitor GSK2578215A (1 μM, 24 hours). In conclusion, Lrrk2 is a powerful regulator of Na+/K+-ATPase expression and activity in dendritic cells.
authors.affiliation: Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.|Experimental Retinal Prosthetics Group, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Hosseinzadeh
authors.affiliation: Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Singh
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.|National Contest for Life (NCL) Foundation, 203555 Hamburg, Germany.
authors.forename: Herman
authors.initials: H
authors.lastname: van der Putten
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.affiliation: Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase