Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurosci
2008 Nov 26;2848:12938-45. doi: 10.1523/JNEUROSCI.3038-08.2008.
Show Gene links
Show Anatomy links
Phosphoinositides regulate P2X4 ATP-gated channels through direct interactions.
Bernier LP
,
Ase AR
,
Chevallier S
,
Blais D
,
Zhao Q
,
Boué-Grabot E
,
Logothetis D
,
Séguéla P
.
???displayArticle.abstract???
P2X receptors are ATP-gated nonselective cation channels highly permeable to calcium that contribute to nociception and inflammatory responses. The P2X(4) subtype, upregulated in activated microglia, is thought to play a critical role in the development of tactile allodynia following peripheral nerve injury. Posttranslational regulation of P2X(4) function is crucial to the cellular mechanisms of neuropathic pain, however it remains poorly understood. Here, we show that the phosphoinositides PI(4,5)P(2) (PIP(2)) and PI(3,4,5)P(3) (PIP(3)), products of phosphorylation by wortmannin-sensitive phosphatidylinositol 4-kinases and phosphatidylinositol 3-kinases, can modulate the function of native and recombinant P2X(4) receptor channels. In BV-2 microglial cells, depleting the intracellular levels of PIP(2) and PIP(3) with wortmannin significantly decreased P2X(4) current amplitude and P2X(4)-mediated calcium entry measured in patch clamp recordings and ratiometric ion imaging, respectively. Wortmannin-induced depletion of phosphoinositides in Xenopus oocytes decreased the current amplitude of P2X(4) responses by converting ATP into a partial agonist. It also decreased their recovery from desensitization and affected their kinetics. Injection of phosphoinositides in wortmannin-treated oocytes reversed these effects and application of PIP(2) on excised inside-out macropatches rescued P2X(4) currents from rundown. Moreover, we report the direct interaction of phospholipids with the proximal C-terminal domain of P2X(4) subunit (Cys(360)-Val(375)) using an in vitro binding assay. These results demonstrate novel regulatory roles of the major signaling phosphoinositides PIP(2) and PIP(3) on P2X(4) function through direct channel-lipid interactions.
Bernier,
Direct modulation of P2X1 receptor-channels by the lipid phosphatidylinositol 4,5-bisphosphate.
2008, Pubmed,
Xenbase
Bernier,
Direct modulation of P2X1 receptor-channels by the lipid phosphatidylinositol 4,5-bisphosphate.
2008,
Pubmed
,
Xenbase
Coull,
Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.
2003,
Pubmed
Coull,
BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain.
2005,
Pubmed
Egan,
Contribution of calcium ions to P2X channel responses.
2004,
Pubmed
Fountain,
A C-terminal lysine that controls human P2X4 receptor desensitization.
2006,
Pubmed
Frank,
Rapid isolation of highly enriched and quiescent microglia from adult rat hippocampus: immunophenotypic and functional characteristics.
2006,
Pubmed
Fujiwara,
Regulation of the desensitization and ion selectivity of ATP-gated P2X2 channels by phosphoinositides.
2006,
Pubmed
,
Xenbase
Grynkiewicz,
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
1985,
Pubmed
Guo,
Evidence for functional P2X4/P2X7 heteromeric receptors.
2007,
Pubmed
Hanisch,
Microglia as a source and target of cytokines.
2002,
Pubmed
Hide,
Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia.
2000,
Pubmed
Hilgemann,
The complex and intriguing lives of PIP2 with ion channels and transporters.
2001,
Pubmed
Inoue,
ATP- and adenosine-mediated signaling in the central nervous system: chronic pain and microglia: involvement of the ATP receptor P2X4.
2004,
Pubmed
Khakh,
Allosteric control of gating and kinetics at P2X(4) receptor channels.
1999,
Pubmed
,
Xenbase
Lawson,
Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain.
1990,
Pubmed
Lê,
Central P2X4 and P2X6 channel subunits coassemble into a novel heteromeric ATP receptor.
1998,
Pubmed
,
Xenbase
Nakanishi,
A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids.
1995,
Pubmed
Nicke,
Biochemical and functional evidence for heteromeric assembly of P2X1 and P2X4 subunits.
2005,
Pubmed
,
Xenbase
North,
Molecular physiology of P2X receptors.
2002,
Pubmed
Pochynyuk,
Regulation of the epithelial Na+ channel (ENaC) by phosphatidylinositides.
2006,
Pubmed
Priel,
Mechanism of ivermectin facilitation of human P2X4 receptor channels.
2004,
Pubmed
Raouf,
Differential regulation of microglial P2X4 and P2X7 ATP receptors following LPS-induced activation.
2007,
Pubmed
Ren,
Differential expression of inflammatory mediators in rat microglia cultured from different brain regions.
1999,
Pubmed
Rohács,
Specificity of activation by phosphoinositides determines lipid regulation of Kir channels.
2003,
Pubmed
,
Xenbase
Rohács,
PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain.
2005,
Pubmed
Rosenhouse-Dantsker,
Molecular characteristics of phosphoinositide binding.
2007,
Pubmed
Royle,
Non-canonical YXXGPhi endocytic motifs: recognition by AP2 and preferential utilization in P2X4 receptors.
2005,
Pubmed
Rubio,
Distinct Localization of P2X receptors at excitatory postsynaptic specializations.
2001,
Pubmed
Shigemoto-Mogami,
Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5.
2001,
Pubmed
Srivastava,
The phosphatidylinositol 3-phosphate phosphatase myotubularin- related protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+ channel KCa3.1.
2005,
Pubmed
Suh,
Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate.
2005,
Pubmed
Suh,
PIP2 is a necessary cofactor for ion channel function: how and why?
2008,
Pubmed
Thyagarajan,
Hydrolysis of phosphatidylinositol 4,5-bisphosphate mediates calcium-induced inactivation of TRPV6 channels.
2008,
Pubmed
Toulmé,
Functional properties of internalization-deficient P2X4 receptors reveal a novel mechanism of ligand-gated channel facilitation by ivermectin.
2006,
Pubmed
Townsend-Nicholson,
Molecular cloning, functional characterization and possible cooperativity between the murine P2X4 and P2X4a receptors.
1999,
Pubmed
,
Xenbase
Trang,
Purinoceptors in microglia and neuropathic pain.
2006,
Pubmed
Tsuda,
P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.
2003,
Pubmed
Vanhaesebroeck,
Synthesis and function of 3-phosphorylated inositol lipids.
2001,
Pubmed
Zhainazarov,
Modulation of the olfactory CNG channel by Ptdlns(3,4,5)P3.
2004,
Pubmed
Zhao,
PIP(2) regulates the ionic current of P2X receptors and P2X(7) receptor-mediated cell death.
2007,
Pubmed
