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Leucine-Rich Repeat Kinase 2 (Lrrk2)-Sensitive Na$^+$/K$^+$ ATPase Activity in Dendritic Cells


Hosseinzadeh, Zohreh; Singh, Yogesh; Shimshek, Derya R; van der Putten, Herman; Wagner, Carsten A; Lang, Florian (2017). Leucine-Rich Repeat Kinase 2 (Lrrk2)-Sensitive Na$^+$/K$^+$ ATPase Activity in Dendritic Cells. Scientific Reports, 7:41117.

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$^+$/Ca$^+$-exchanger activity. The elimination of Ca$^{2+}$ by Na$^+$/Ca$^{2+}$-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.

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$^+$/Ca$^+$-exchanger activity. The elimination of Ca$^{2+}$ by Na$^+$/Ca$^{2+}$-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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:25 January 2017
Deposited On:22 Mar 2017 13:04
Last Modified:19 Feb 2018 07:47
Publisher:Nature Publishing Group
ISSN:2045-2322
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/srep41117
PubMed ID:28120865

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