QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 16 October 2007
doi: 10.1242/jcs.010348

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: jcs.010348v1 120/21/3838    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qureshi, O. S. Articles by Murrell-Lagnado, R. D. Search for Related Content PubMed PubMed Citation Articles by Qureshi, O. S. Articles by Murrell-Lagnado, R. D. Social Bookmarking                         What's this?

Regulation of P2X₄ receptors by lysosomal targeting, glycan protection and exocytosis

Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK

^* Author for correspondence (e-mail: rdm1003{at}cam.ac.uk)

Accepted 23 August 2007

The P2X₄ receptor has a widespread distribution in the central nervous system and the periphery, and plays an important role in the function of immune cells and the vascular system. Its upregulation in microglia contributes to neuropathic pain following nerve injury. The mechanisms involved in its regulation are not well understood, although we have previously shown that it is constitutively retrieved from the plasma membrane and resides predominantly within intracellular compartments. Here, we show that the endogenous P2X₄ receptors in cultured rat microglia, vascular endothelial cells and freshly isolated peritoneal macrophages are localized predominantly to lysosomes. Lysosomal targeting was mediated through a dileucine-type motif within the N-terminus, together with a previously characterized tyrosine-based endocytic motif within the C-terminus. P2X₄ receptors remained stable within the proteolytic environment of the lysosome and resisted degradation by virtue of their N-linked glycans. Stimulation of phagocytosis triggered the accumulation of P2X₄ receptors at the phagosome membrane. Stimulating lysosome exocytosis, either by incubating with the Ca²⁺ ionophore ionomycin, for normal rat kidney (NRK) cells and cultured rat microglia, or the weak base methylamine, for peritoneal macrophages, caused an upregulation of both P2X₄ receptors and the lysosomal protein LAMP-1 at the cell surface. Lysosome exocytosis in macrophages potentiated ATP-evoked P2X₄ receptor currents across the plasma membrane. Taken together, our data suggest that the P2X₄ receptor retains its function within the degradative environment of the lysosome and can subsequently traffic out of lysosomes to upregulate its exposure at the cell surface and phagosome.

Key words: Lysosome, P2X, Macrophage, Phagosome, Endocytosis

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

Related articles in JCS:

Lysosomal hideaway for ATP receptors

JCS 2007 120: 2102. [Full Text]  

This article has been cited by other articles:

				R. Hazama, X. Qu, K. Yokoyama, C. Tanaka, E. Kinoshita, J. He, S. Takahashi, K. Tohyama, H. Yamamura, and Y. Tohyama ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk Genes Cells, July 1, 2009; 14(7): 871 - 884. [Abstract] [Full Text] [PDF]

				R. Murrell-Lagnado More cross-talk between purinergic receptors J. Physiol., June 15, 2009; 587(12): 2713 - 2714. [Full Text] [PDF]

				M. Boumechache, M. Masin, J. M. Edwardson, D. C. Gorecki, and R. Murrell-Lagnado Analysis of Assembly and Trafficking of Native P2X4 and P2X7 Receptor Complexes in Rodent Immune Cells J. Biol. Chem., May 15, 2009; 284(20): 13446 - 13454. [Abstract] [Full Text] [PDF]