Mutations in the E3 ubiquitin ligase parkin cause early-onset, autosomal-recessive juvenile parkinsonism (AJRP), presumably as a result of a lack of function that alters the level, activity, aggregation or localization of its substrates. Recently, we have reported that phospholipase Cγ1 is a substrate for parkin. In this article, we show that parkin mutants and siRNA parkin knockdown cells possess enhanced levels of phospholipase Cγ1 phosphorylation, basal phosphoinositide hydrolysis and intracellular Ca 2+ concentration. The protein levels of Ca2+-regulated protein kinase Cα were decreased in AJRP parkin mutant cells. Neomycin and dantrolene both decreased the intracellular Ca2+ levels in parkin mutants in comparison with those seen in wild-type parkin cells, suggesting that the differences were a consequence of altered phospholipase C activity. The protection of wild-type parkin against 6-hydroxydopamine (6OHDA) toxicity was also established in ARJP mutants on pretreatment with dantrolene, implying that a balancing Ca2+ release from ryanodine-sensitive stores decreases the toxic effects of 6OHDA. Our findings suggest that parkin is an important factor for maintaining Ca2+ homeostasis and that parkin deficiency leads to a phospholipase C-dependent increase in intracellular Ca2+ levels, which make cells more vulnerable to neurotoxins, such as 6OHDA. © 2009 FEBS.
CITATION STYLE
Sandebring, A., Dehvari, N., Perez-Manso, M., Thomas, K. J., Karpilovski, E., Cookson, M. R., … Cedazo-Mínguez, A. (2009). Parkin deficiency disrupts calcium homeostasis by modulating phospholipase C signalling. FEBS Journal, 276(18), 5041–5052. https://doi.org/10.1111/j.1742-4658.2009.07201.x
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