Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion

Cao, Qi, Zhong, Xi Zoë, Zou, Yuanjie, Murrell-Lagnado, Ruth, Zhu, Michael X and Dong, Xian-Ping (2015) Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion. Journal of Cell Biology, 209 (6). pp. 879-894. ISSN 1540-8140

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Intra-endolysosomal Ca(2+) release is required for endolysosomal membrane fusion with intracellular organelles. However, the molecular mechanisms for intra-endolysosomal Ca(2+) release and the downstream Ca(2+) targets involved in the fusion remain elusive. Previously, we demonstrated that endolysosomal P2X4 forms channels activated by luminal adenosine triphosphate in a pH-dependent manner. In this paper, we show that overexpression of P2X4, as well as increasing endolysosomal P2X4 activity by alkalinization of endolysosome lumen, promoted vacuole enlargement in cells and endolysosome fusion in a cell-free assay. These effects were prevented by inhibiting P2X4, expressing a dominant-negative P2X4 mutant, and disrupting the P2X4 gene. We further show that P2X4 and calmodulin (CaM) form a complex at endolysosomal membrane where P2X4 activation recruits CaM to promote fusion and vacuolation in a Ca(2+)-dependent fashion. Moreover, P2X4 activation-triggered fusion and vacuolation were suppressed by inhibiting CaM. Our data thus suggest a new molecular mechanism for endolysosomal membrane fusion involving P2X4-mediated endolysosomal Ca(2+) release and subsequent CaM activation.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology
Depositing User: Ruth Murrell-Lagnado
Date Deposited: 19 Feb 2016 12:39
Last Modified: 24 Nov 2020 10:39

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