Pharmacology Of P2X Receptors Research Articles

TMEM163 Regulates ATP-Gated P2X Receptor and Behavior

Fast purinergic signaling is mediated by ATP and ATP-gated ionotropic P2X receptors (P2XRs), and it is implicated in pain-related behaviors. The properties exhibited by P2XRs vary between those expressed in heterologous cells and invivo. Several modulators of ligand-gated ion channels have recently been identified, suggesting that there are P2XR functional modulators invivo. Here, we establish a genome-wide open reading frame (ORF) collection and perform functional screening to identify modulators of P2XR activity. We identify TMEM163, which specifically modulates the channel properties and pharmacology of P2XRs. We also find that TMEM163 is required for full function of the neuronal P2XR and a pain-related ATP-evoked behavior. These results establish TMEM163 as a critical modulator of P2XRs invivo and a potential target for the discovery of drugs for treating pain.

Pharmacology of P2X receptors

AbstractP2X receptors are ligand‐gated cation channels that mediate many of the extracellular actions of adenosine 5′‐triphosphate (ATP). The genes encoding seven different P2X subunits, P2X1–7, have been cloned and when expressed alone all P2X subunits form functional receptors, except P2X6, which usually only assembles in a heteromeric form. Subunits can also interact with each other and to date seven functional heteromultimers with pharmacological and/or biophysical properties that differ from the individual homomultimers have been identified: P2X2/3, P2X4/6, P2X1/5, P2X2/6, P2X1/4, P2X1/2, and possibly P2X4/7. These are distributed widely throughout the body and are involved in many physiological and pathophysiological processes. ATP is an agonist at all subtypes and few selective agonists and no useful antagonists were available when P2X receptors were first defined. Subsequently, nonselective antagonists, such as suramin and PPADS, were discovered and since then, and particularly in the past decade, numerous potent and subtype‐selective antagonists have been developed. These include NF449 and RO‐1 at P2X1 receptors; PSB‐1011 at P2X2 receptors; A317491, compound A, RO‐3, and AF‐353 at P2X3 and P2X2/3 receptors; 5‐BDBD at P2X4 receptors; and A740003, A438079, A804598, GSK314181A, AZ10606120, AZ11645373, AZD‐9056, CE‐224535, and EVT‐401 at P2X7 receptors. The therapeutic usefulness of these compounds is currently being investigated in a variety of disorders, including thrombosis (P2X1), chronic neuropathic and inflammatory pain (P2X3, P2X2/3, P2X4, P2X7), dysfunctional urinary bladder (P2X1, P2X3, P2X2/3), rheumatoid arthritis and osteoarthritis (P2X7), and depression (P2X7). WIREs Membr Transp Signal 2012, 1:16–30. doi: 10.1002/wmts.1For further resources related to this article, please visit the WIREs website.