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.
Highlights
Leucine-rich repeat kinase 2 (Lrrk2) has been implicated in the pathophysiology of Parkinson’s disease (PD)[1,2,3]
dendritic cells (DCs) were isolated from gene-targeted mice lacking Lrrk[2] (Lrrk2−/−) and their wild-type littermates (Lrrk2+/+) and Na+/K+ ATPase expression at mRNA and protein levels determined by RT-PCR and Western blotting, respectively
The present study explored, whether Lrrk[2] has an impact on the Na+/K+ -ATPase activity in DCs
Summary
Leucine-rich repeat kinase 2 (Lrrk2) has been implicated in the pathophysiology of Parkinson’s disease (PD)[1,2,3]. According to recent observations Lrrk[2] up-regulates Na+/Ca2+ -exchanger expression and activity in DCs blunting Ca2+ -signals and attenuating Ca2+ -dependent functions of DCs20. Na+/Ca2+ -exchanger function requires maintenance of the Na+ gradient across the cell membrane, a function of the Na+/K+ ATPase[21]. The extent that a function of Lrrk[2] is the stimulation of Ca2+ extrusion by up-regulation of Na+/Ca2+ -exchangers, the efficacy of the kinase requires adequate Na+/K+ ATPase activity. We hypothesized that Lrrk[2] may, in addition to its effect on Na+/Ca2+ -exchange, up-regulate Na+/K+ ATPase activity. The up-regulation of Na+/K+ ATPase activity contributes to the maintenance of the steep electrochemical Na+ gradient required for Ca2+ extrusion by the Na+/ Ca2+ -exchanger
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