P2X4 receptor channels form large noncytolytic pores in resting and activated microglia.
Glia. 2012-02-08; 60(5): 728-737
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1. Glia. 2012 May;60(5):728-37. doi: 10.1002/glia.22301. Epub 2012 Feb 8.
P2X4 receptor channels form large noncytolytic pores in resting and activated
Bernier LP(1), Ase AR, Boué-Grabot E, Séguéla P.
(1)Department of Neurology & Neurosurgery, Montreal Neurological Institute, Alan
Edwards Center for Research on Pain, McGill University, Montréal, Québec, Canada.
P2X4 ATP-gated cation channels have been shown to contribute to the microglial
component of central sensitization, making their functional regulation a key
element in chronic pain pathologies. Here we show that prolonged activation of
native P2X4 receptor channels by ATP induces opening of a pore permeable to
NMDG(+) and large fluorescent dyes in BV-2 microglial cells and primary murine
microglia. This intrinsic pore formation mechanism is potentiated by LPS
treatment, known to upregulate P2X4 expression in microglial cells and to mimic
the microglial activation observed in neuropathic pain states. Sustained
activation of the P2X7 channel subtype, also expressed in microglia, induces a
pore formation that requires pannexin hemichannels and leads to plasma membrane
blebbing and cytotoxicity. In contrast, P2X4 pore formation is unaffected by the
pannexin blocker carbenoxolone, does not induce cytoskeletal rearrangements and
does not lead to cell death. Furthermore, we show that P2X4 pore dilation is
modulated by phosphoinositides (PIP(n) ) levels as it is inhibited by wortmannin,
a blocker of PIP(n) synthesis, suggesting possible regulation by phospholipase
C-coupled pathways. Nonlethal P2X4 pore dilation could play a role in neuropathic
pain by allowing the flux of large organic molecules in microglia. Different
outcomes of P2X4 and P2X7 membrane permeabilization point to subtype-specific
microglial responses to ATP in normal and pathological neuro-immune crosstalks.
Copyright © 2012 Wiley Periodicals, Inc.
PMID: 22318986 [Indexed for MEDLINE]