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

Abstract

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
URI:	https://oak.novartis.com/id/eprint/22495