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The Journal of Neuroscience, November 26, 2008, 28(48):12938-12945; doi:10.1523/JNEUROSCI.3038-08.2008

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Cellular/Molecular
Phosphoinositides Regulate P2X₄ ATP-Gated Channels through Direct Interactions

Louis-Philippe Bernier,¹ Ariel R. Ase,¹ Stéphanie Chevallier,¹ Dominique Blais,¹ Qi Zhao,² Éric Boué-Grabot,³ Diomedes Logothetis,² and Philippe Séguéla¹

¹Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada H3A 2B4, ²Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York University, New York, New York 10029, and ³Université de Bordeaux 2, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, 33076 Bordeaux, France

Correspondence should be addressed to Dr. Philippe Séguéla, Montreal Neurological Institute, 3801 University, Suite 778, Montréal, Québec, Canada H3A 2B4. Email: philippe.seguela{at}mcgill.ca

P2X receptors are ATP-gated nonselective cation channels highly permeable to calcium that contribute to nociception and inflammatory responses. The P2X₄ 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 P2X₄ function is crucial to the cellular mechanisms of neuropathic pain, however it remains poorly understood. Here, we show that the phosphoinositides PI(4,5)P₂ (PIP₂) and PI(3,4,5)P₃ (PIP₃), products of phosphorylation by wortmannin-sensitive phosphatidylinositol 4-kinases and phosphatidylinositol 3-kinases, can modulate the function of native and recombinant P2X₄ receptor channels. In BV-2 microglial cells, depleting the intracellular levels of PIP₂ and PIP₃ with wortmannin significantly decreased P2X₄ current amplitude and P2X₄-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 P2X₄ 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 PIP₂ on excised inside-out macropatches rescued P2X₄ currents from rundown. Moreover, we report the direct interaction of phospholipids with the proximal C-terminal domain of P2X₄ subunit (Cys₃₆₀–Val₃₇₅) using an in vitro binding assay. These results demonstrate novel regulatory roles of the major signaling phosphoinositides PIP₂ and PIP₃ on P2X₄ function through direct channel–lipid interactions.

Key words: P2X; purinergic; PIP₂; calcium; microglia; neuropathic pain

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Received July 1, 2008; revised Oct. 10, 2008; accepted Oct. 14, 2008.

Correspondence should be addressed to Dr. Philippe Séguéla, Montreal Neurological Institute, 3801 University, Suite 778, Montréal, Québec, Canada H3A 2B4. Email: philippe.seguela{at}mcgill.ca

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