Implication of Neuronal Versus Microglial P2X4 Receptors in Central Nervous System Disorders
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REVIEW
Implication of Neuronal Versus Microglial P2X4 Receptors in Central Nervous System Disorders Alexia Duveau1,2 • Ele´onore Bertin1,2 • Eric Boue´-Grabot1,2
Received: 18 February 2020 / Accepted: 6 May 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
Abstract The P2X4 receptor (P2X4) is an ATP-gated cation channel that is highly permeable to Ca2? and widely expressed in neuronal and glial cell types throughout the central nervous system (CNS). A growing body of evidence indicates that P2X4 plays key roles in numerous central disorders. P2X4 trafficking is highly regulated and consequently in normal situations, P2X4 is present on the plasma membrane at low density and found mostly within intracellular endosomal/lysosomal compartments. An increase in the de novo expression and/or surface density of P2X4 has been observed in microglia and/or neurons during pathological states. This review aims to summarize knowledge on P2X4 functions in CNS disorders and provide some insights into the relative contributions of neuronal and glial P2X4 in pathological contexts. However, determination of the cell-specific functions of P2X4 along with its intracellular and cell surface roles remain to be elucidated before its potential as a therapeutic target in multiple disorders can be defined. Keywords Purinergic signaling P2X ATP Ligandgated ion channels Chronic pain Brain trauma Ischemia Neurodegenerative diseases Alcohol Neuropsychiatric disorders
& Eric Boue´-Grabot [email protected] 1
Universite´ de Bordeaux, Institut des Maladies Neurode´ge´ne´ratives, UMR 5293, 33000 Bordeaux, France
2
CNRS, Institut des Maladies Neurode´ge´ne´ratives, UMR 5293, 33000 Bordeaux, France
Introduction Initially discovered as one of the main sources of energy inside cells, adenosine 5’ triphosphate (ATP) is now recognized as a ubiquitous extracellular cell-to-cell signaling molecule in the peripheral (PNS) and central nervous system (CNS), as well as in peripheral organs [1]. Although the release of ATP by sensory nerve cells was reported in the 1950s [2], Geoffrey Burnstock was the first to propose the concept of purinergic signaling using ATP as a fast neurotransmitter in 1972 [3]. ATP was later shown to mediate fast neurotransmission in the PNS and CNS alike, but is nowadays mostly considered to be a neuromodulator co-released with other classical neurotransmitters such as GABA or glutamate at inhibitory or excitatory synapses in the CNS [4]. ATP is also a gliotransmitter released by glial cell types such as astrocytes and microglia [5–7]. ATP released by neurons and glia exerts multiple actions in the neuromodulation of synaptic activity and plasticity, communication in glial networks, and directly between glia and neurons via the activation of metabotropic P2Y and ionotropic P2X receptors, or after the conversion of ATP by ectonucleotidases into ADP and adenosine by the activation of P2Y and adenosine P1 receptors [4, 8]. There is also growing evidenc
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