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LRRK2 sensitive Na+/Ca2+ exchanger activity in dendritic cells

Yan, Jing and Almilaji, Ahmad and Schmid, Evi and Shimshek, Derya and Van Der Putten, P. Herman and Wagner, Carsten and Shumilina, Ekaterina and Lang, Florian (2015) LRRK2 sensitive Na+/Ca2+ exchanger activity in dendritic cells. The Federation of American Societies for Experimental Biology Journal.


Gene variants of the leucine-rich repeat kinase 2 (LRRK2) are associated with susceptibility to Parkinson's disease, Crohn's disease and leprosy. The kinase is expressed in several immune cells including dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. The function of LRRK2 remained, however, incompletely understood. To gain insight into LRRK2 sensitive functions, Ca2+ signaling was analysed in DCs isolated from gene targeted mice lacking functional lrrk2 (lrrk2-/-) and their wild type littermates (lrrk2+/+). Cytosolic Ca2+ activity ([Ca2+]i) was determined utilizing Fura-2 fluorescence and whole cell currents to decipher electrogenic transport. The increase of [Ca2+]i following inhibition of sarcoendoplasmatic Ca2+ ATPase in the absence of extracellular Ca2+ were significantly larger in lrrk2-/- than in lrrk2+/+ DCs. At least in theory, the increase of [Ca2+]i could be augmented by impaired Ca2+ extrusion due to decreased Na+/Ca2+ exchanger activity. To quantify the activity of the K+-independent and K+-dependent Na+/Ca2+ exchanger activity (I and jin used different solutions), the increase of [Ca2+]i (Δ[Ca2+]i) and Na+/Ca2+ exchanger induced current (Ica) were determined during abrupt replacement of Na+ containing (130 mM) and Ca2+ free (0 mM) extracellular perfusate by Na+ free (0 mM) and Ca2+ containing (2 mM) extracellular perfusate. As a result, both slope and peak of Δ[Ca2+]i as well as Ica were significantly lower in lrrk2-/- than in lrrk2+/+ DCs. In conclusion, LRRK2 defciency leads to downregulation of Na+/Ca2+ exchanger activity and thus augmentation of Ca2+ signals in DCs. The present observations thus disclose a completely novel functional significance of LRRK2.

Item Type: Article
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12


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