Inhibition of P2X4 function by P2Y6 UDP receptors in microglia.
Glia. 2013-10-07; 61(12): 2038-2049
DOI: 10.1002/glia.22574
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1. Glia. 2013 Dec;61(12):2038-49. doi: 10.1002/glia.22574. Epub 2013 Oct 7.
Inhibition of P2X4 function by P2Y6 UDP receptors in microglia.
Bernier LP(1), Ase AR, Boué-Grabot É, Séguéla P.
Author information:
(1)Department of Neurology and Neurosurgery, Montreal Neurological Institute,
Alan Edwards Center for Research on Pain, McGill University, Montréal, Québec,
H3A 2B4, Canada.
ATP-gated P2X4 receptor channels expressed in spinal microglia actively
participate in central sensitization, making their functional regulation a key
process in chronic pain pathologies. P2Y6 metabotropic Gq -coupled receptors,
also expressed in microglia, are involved in the initial response to nerve
injury, triggering phagocytosis upon activation by UDP. It has been reported
recently that expression of both P2X4 and P2Y6 is upregulated in activated
microglia following nerve injury. We show here, in resting as well as
LPS-activated primary microglia, that P2Y6 decreases P2X4-mediated calcium entry
and inhibits the dilation of P2X4 channels into a large-conductance pore measured
with a YO-PRO-1 uptake assay. Furthermore, P2Y6 activation modulates the
ATP-dependent migration of microglia, a process likely involved in their shift
from migratory to phagocytic phenotype. Reconstituting the P2X4-P2Y6 interaction
in recombinant systems shows that P2Y6 activation decreases P2X4 current
amplitude, activation and desensitization rates, and reduces P2X4 channel
permeability to the large cation NMDG(+) . Phospholipase C-mediated hydrolysis of
the phosphoinositide PI(4,5)P2 , a necessary cofactor for P2X4 channel function,
underlies this inhibitory crosstalk. As extracellular levels of both ATP and UDP
are increased in the spinal cord following nerve injury, the control of P2X4
activity by P2Y6 might play a critical role in regulating neuropathic
pain-inducing microglial responses.
Copyright © 2013 Wiley Periodicals, Inc.
DOI: 10.1002/glia.22574
PMID: 24123515 [Indexed for MEDLINE]