Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons

Abstract

Cation-selective P2X receptor channels were first described in sensory neurons where they are important for primary afferent neurotransmission and nociception. Here we report the cloning of a complementary DNA (P2X3) from rat dorsal root ganglia that had properties dissimilar to those of sensory neurons. We also found RNA for (P2X1)(ref. 7), (P2X2)(ref. 8) and P2X4 (ref. 9) in sensory neurons; channels expressed from individual cDNAs did not reproduce those of sensory ganglia. Coexpression of P2X3 with P2X2, but not other combinations, yielded ATP-activated currents that closely resembled those in sensory neurons. These properties could not be accounted for by addition of the two sets of channels, indicating that a new channel had formed by subunit heteropolymerization. Although in some tissues responses to ATP can be accounted for by homomeric channels, our results indicate that ATP-gated channels of sensory neurons may form by a specific heteropolymerization of P2X receptor subunits.

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

“…The P2X3 receptors were cloned in 1995 [27,28], and they are almost exclusively localized to nociceptive sensory ganglion neurons and nodose ganglion neurons [29,30]. Different chronic pain diseases are linked to the upregulation of these Electronic supplementary material The online version of this article (doi:10.1007/s11302-016-9539-y) contains supplementary material, which is available to authorized users.…”

Molecular cloning and functional expression of a novel rat heart P2X purinoceptor

“…All these effects are apparently mediated by a miscellaneous group of G-protein coupled receptors (P2Y) and ligand-gated channels (P2X) [4]. To date, despite the numerous functions attributed to extracellular ATP, only four P2X receptors have been identified: P2X1 [5], P2X2 [6], P2X3 [7,8] and P2X4 [9][10][11][12][13]. Analysis of the amino acid sequences provides evidence of a novel family of membrane proteins consisting of two short intracellular domains, two transmembrane-spanning motifs, and a large extracellular loop comprising 10 conserved cysteines.…”

“…In addition to expressing P2X3 receptors, these neurons also hold transcripts of all P2X1 to 4 isoforms. Indeed, P2X2/P2X3 heteromultimeric receptors have been proposed to occur in vivo [7]. This raises the fascinating possibility that ATP is involved in the generation of pain signals [7,8,16].…”

“…Heterologous expression of each recombinant P2X isoform results in ATP-activated cation-selective channels with diverse pharmacological and desensitization phenotypes [5][6][7][8][9][10][11][12][13]17]. The main pharmacological distinction is their the relative sensitivities to the agonist a,13-meATP and the antagonists suramin and PPADS.…”

“…The main pharmacological distinction is their the relative sensitivities to the agonist a,13-meATP and the antagonists suramin and PPADS. Thus, a,13-meATP is a full agonist for P2X1 and P2X3 receptors [5,7,8,17], but is not effective on the P2X2 and P2X4 forms [9][10][11][12][13]17]. On the other hand, P2X4 is the only purinergic receptor cloned so far that is insensitive to the established P2X blockers suramin and PPADS [9,10,12,13].…”