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Leucine-rich repeat kinase 2-sensitive Na+/K+ ATPase activity in dendritic cells

Hosseinzadeh, Zohreh and Singh, Yogesh and Yan, Jing and Shimshek, Derya and Van Der Putten, P. Herman and Wagner, Carsten and Lang, Florian (2015) Leucine-rich repeat kinase 2-sensitive Na+/K+ ATPase activity in dendritic cells. FASEB, 29 (5). pp. 1701-1710. ISSN 1530-6860

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathophysiology of Parkinson's disease. A variety of cells express LRRK2 including neurons and dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. Most recently, LRRK2 has been shown to up-regulate Na+/Ca2+-exchanger activity in DCs. 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-PCR 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 was in lrrk2+/+ DCs significantly blunted by the 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 the LRRK2 inhibitor GSK2578215A (1 µM, 24 hours). In conclusion, LRRK2 is a powerful regulator of Na+/K+-ATPase expression and activity.

Item Type: Article
Date Deposited: 23 Mar 2016 00:45
Last Modified: 23 Mar 2016 00:45
URI: https://oak.novartis.com/id/eprint/27991

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