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

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.