AUTHOR=Bernier Louis-Philippe , Ase Ariel , Seguela Philippe 

TITLE=Post-translational regulation of P2X receptor channels: modulation by phospholipids

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=7

YEAR=2013

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2013.00226

DOI=10.3389/fncel.2013.00226

ISSN=1662-5102

ABSTRACT=<p>P2X receptor channels mediate fast excitatory signaling by ATP and play major roles in sensory transduction, neuro-immune communication and inflammatory response. P2X receptors constitute a gene family of calcium-permeable ATP-gated cation channels therefore the regulation of P2X signaling is critical for both membrane potential and intracellular calcium homeostasis. Phosphoinositides (PIP<sub>n</sub>) are anionic signaling phospholipids that act as functional regulators of many types of ion channels. Direct PIP<sub>n</sub> binding was demonstrated for several ligand- or voltage-gated ion channels, however no generic motif emerged to accurately predict lipid-protein binding sites. This review presents what is currently known about the modulation of the different P2X subtypes by phospholipids and about critical determinants underlying their sensitivity to PIP<sub>n</sub> levels in the plasma membrane. All functional mammalian P2X subtypes tested, with the notable exception of P2X5, have been shown to be positively modulated by PIP<sub>n</sub>, i.e., homomeric P2X1, P2X2, P2X3, P2X4, and P2X7, as well as heteromeric P2X1/5 and P2X2/3 receptors. Based on various results reported on the aforementioned subtypes including mutagenesis of the prototypical PIP<sub>n</sub>-sensitive P2X4 and PIP<sub>n</sub>-insensitive P2X5 receptor subtypes, an increasing amount of functional, biochemical and structural evidence converges on the modulatory role of a short polybasic domain located in the proximal C-terminus of P2X subunits. This linear motif, semi-conserved in the P2X family, seems necessary and sufficient for encoding direct modulation of ATP-gated channels by PIP<sub>n</sub>. Furthermore, the physiological impact of the regulation of ionotropic purinergic responses by phospholipids on pain pathways was recently revealed in the context of native crosstalks between phospholipase C (PLC)-linked metabotropic receptors and P2X receptor channels in dorsal root ganglion sensory neurons and microglia.</p>