P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology

Abstract

Adenosine 5′-triphosphate is a well-known extracellular signaling molecule and neurotransmitter known to activate purinergic P2X receptors. Information has been elucidated about the structure and gating of P2X channels following the determination of the crystal structure of P2X4 (zebrafish), however, there is still much to discover regarding the role of this receptor in the central nervous system (CNS). In this review we provide an overview of what is known about P2X4 expression in the CNS and discuss evidence for pathophysiological roles in neuroinflammation and neuropathic pain. Recent advances in the development of pharmacological tools including selective antagonists (5-BDBD, PSB-12062, BX430) and positive modulators (ivermectin, avermectins, divalent cations) of P2X4 will be discussed.

Involvement of purinergic 2X4 receptor in glycoprotein 120‐induced pyroptosis in dorsal root ganglia

“…In our study, treatment with P2X 4 shRNA could effectively counteract gp120‐promoted production of NO and ROS in SGCs of DRG. Moreover, it is well known that activation of p38MAPK is a critical mechanism for P2X 4 receptor signaling pathways to participate in neuropathic pain (de Rivero Vaccari et al ; Stokes et al ). The phosphorylation of p38MAPK is the marker of its activation.…”

“…As a signaling molecule, extracellular adenosine 5'triphosphate (ATP) plays multiple roles in both health maintenance and disease development (Burnstock 2007;Surprenant and North 2009;Stokes et al 2017). Purinergic 2X (P2X) receptors are cationic channels gated by extracellular ATP, and involved in immune regulation, apoptosis, and neurotransmission (Burnstock and Knight 2004;Burnstock 2007;Surprenant and North 2009).…”

“…Purinergic 2X (P2X) receptors are cationic channels gated by extracellular ATP, and involved in immune regulation, apoptosis, and neurotransmission (Burnstock and Knight 2004;Burnstock 2007;Surprenant and North 2009). There are seven identified mammalian P2X receptor subtypes (P2X 1 -P2X 7 ) (Burnstock and Knight 2004;Burnstock 2007;Surprenant and North 2009;Stokes et al 2017). The purinergic 2X 4 (P2X 4 ) receptor is implicated in neuropathic pain and inflammatory pain (Ulmann et al 2008;Ulmann et al 2010;Tsuda et al 2013;Stokes et al 2017).…”

“…There are seven identified mammalian P2X receptor subtypes (P2X 1 -P2X 7 ) (Burnstock and Knight 2004;Burnstock 2007;Surprenant and North 2009;Stokes et al 2017). The purinergic 2X 4 (P2X 4 ) receptor is implicated in neuropathic pain and inflammatory pain (Ulmann et al 2008;Ulmann et al 2010;Tsuda et al 2013;Stokes et al 2017). In dorsal root ganglia (DRG), activation of satellite glial cells (SGCs) closely surrounding the cell bodies of neurons occurs after peripheral nerve injury (Hanani 2005;Costa and Neto 2015).…”

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

“…Each subunit has a double transmembrane topology and large extracellular domain which forms the orthosteric ATP binding site with an adjacent subunit (Kawate, Michel, Birdsong, & Gouaux, ; Mansoor et al, ; Wang et al, ). Several P2X receptor subtypes are implicated in pain, irritation, and hypersensitivity and have been proposed as drug targets, including the P2X3 receptor and P2X2/3 heteromeric receptor (Gever et al, ; Jarvis et al, ; Pijacka et al, ; Stokes, Layhadi, Bibic, Dhuna, & Fountain, ). P2X3 receptor tissue expression is very limited with protein and mRNA transcript detected in small diameter C‐fibre sensory neurons (Chen et al, ; Lewis et al, ; Xiang, Bo, & Burnstock, ), particularly those innervating the skin and viscera (Bradbury, Burnstock, & McMahon, ), petrosal neurons, and the carotid body afferents (Pijacka et al, ).…”