摘要：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(2+)-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.
