Subtype-specific regulation of P2X3 and P2X2/3 receptors by phosphoinositides in peripheral nociceptors
<p>Abstract</p> <p>Background</p> <p>P2X3 and P2X2/3 purinergic receptor-channels, expressed in primary sensory neurons that mediate nociception, have been implicated in neuropathic and inflammatory pain responses. The phospholipids phosphatidylinositol 4,5-bisphosphate...
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| Main Authors: | , , , , , , , |
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| Format: | Book |
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SAGE Publishing,
2009-08-01T00:00:00Z.
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| Summary: | <p>Abstract</p> <p>Background</p> <p>P2X3 and P2X2/3 purinergic receptor-channels, expressed in primary sensory neurons that mediate nociception, have been implicated in neuropathic and inflammatory pain responses. The phospholipids phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>) and phosphatidylinositol 3,4,5-trisphosphate (PIP<sub>3</sub>) are involved in functional modulation of several types of ion channels. We report here evidence that these phospholipids are able to modulate the function of homomeric P2X3 and heteromeric P2X2/3 purinoceptors expressed in dorsal root ganglion (DRG) nociceptors and in heterologous expression systems.</p> <p>Results</p> <p>In dissociated rat DRG neurons, incubation with the PI3K/PI4K inhibitor wortmannin at 35 μM induced a dramatic decrease in the amplitude of ATP- or α,β-meATP-evoked P2X3 currents, while incubation with 100 nM wortmannin (selective PI3K inhibition) produced no significant effect. Intracellular application of PIP<sub>2 </sub>was able to fully reverse the inhibition of P2X3 currents induced by wortmannin. In <it>Xenopus </it>oocytes and in HEK293 cells expressing recombinant P2X3, 35 μM wortmannin incubation induced a significant decrease in the rate of receptor recovery. Native and recombinant P2X2/3 receptor-mediated currents were inhibited by incubation with wortmannin both at 35 μM and 100 nM. The decrease of P2X2/3 current amplitude induced by wortmannin could be partially reversed by application of PIP<sub>2 </sub>or PIP<sub>3</sub>, indicating a sensitivity to both phosphoinositides in DRG neurons and <it>Xenopus </it>oocytes. Using a lipid binding assay, we demonstrate that the C-terminus of the P2X2 subunit binds directly to PIP<sub>2</sub>, PIP<sub>3 </sub>and other phosphoinositides. In contrast, no direct binding was detected between the C-terminus of P2X3 subunit and phosphoinositides.</p> <p>Conclusion</p> <p>Our findings indicate a functional regulation of homomeric P2X3 and heteromeric P2X2/3 ATP receptors by phosphoinositides in the plasma membrane of DRG nociceptors, based on subtype-specific mechanisms of direct and indirect lipid sensing.</p> |
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| Item Description: | 10.1186/1744-8069-5-47 1744-8069 |