Alternative titles; symbols
HGNC Approved Gene Symbol: P2RX3
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38): 11:57,335,950-57,372,396 (from NCBI)
The P2RX3 gene encodes a cell-surface purinergic receptor that plays a role in pain perception. ATP is known to depolarize sensory neurons and may play a role in nociceptor activation when released from damaged tissue. Cell surface ATP receptors can be divided into 2 classes: the ionotropic (P2X) class of ligand-gated channels and the metabotropic (P2Y/P2U) class of G protein-coupled receptors (see 602451) that are members of the 7-transmembrane superfamily of G protein-coupled receptors (Kennedy and Leff, 1995).
P2X purinoceptors are 397 to 492 amino acids long and have a predicted structure of 2 short intracellular domains, 2 transmembrane-spanning regions, and a large extracellular domain. The P2RX3 subunit has 43% and 47% identity with P2RX1 (600845) and P2RX2 (600844), respectively; 10 cysteine residues are conserved in all 3 subtypes, so that tertiary structures may also be conserved (Kennedy and Leff, 1995).
Cation-selective PTX receptor channels were first described in sensory neurons where they are important for primary afferent neurotransmission and nociception (pain perception). Chen et al. (1995) reported the molecular cloning and characterization of a new member of the P2X receptor family, P2X3, expressed by sensory neurons. The channel transcript was present in a subset of rat dorsal root ganglion sensory neurons, some of which expressed nociceptor-associated markers; it was absent in other tissues that were tested, including sympathetic, enteric, and CNS neurons. Moreover, when expressed in Xenopus oocytes, the channels showed an ATP-dependent cation flux. P2X3 was the only ligand-gated channel known to be expressed exclusively by a subset of sensory neurons. The remarkable selectivity of expression of the channel, coupled with a sensory neuron-like pharmacology, suggested that it may transduce ATP-evoked nociceptor activation.
Like Chen et al. (1995), Lewis et al. (1995) cloned a cDNA, P2X3, from rat dorsal root ganglia that had properties dissimilar to those of sensory neurons. They also found RNA for P2X1, PRX2, and P2X4 (600846) 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 2 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, the results of Lewis et al. (1995) indicated that ATP-gated channels of sensory neurons may form by a specific heteropolymerization of P2X receptor subunits. This was the first evidence that P2X receptors are multimers, a situation with clear parallels to nicotinic and glutamate receptor channels and voltage-gated potassium channels.
By RT-PCR of heart RNA with degenerate oligonucleotide primers based on P2X receptor sequences, Garcia-Guzman et al. (1997) cloned a cDNA encoding human P2X3. The sequences of the predicted 397-amino acid human protein and rat P2X3 are 93% identical. Using RT-PCR, these authors determined that P2X3 is expressed only in spinal cord and heart. Heterologous expression of human P2X3 in Xenopus oocytes generated a fast-desensitizing ATP-activated channel with pharmacologic properties resembling those of rat P2X3.
Souslova et al. (1997) isolated a full-length mouse P2X3 from a mouse genomic library. The predicted 397-amino acid mouse protein shares 99% identity with rat P2X3. Using RNase protection and primer extension assays, multiple transcription initiation sites were mapped in the mouse P2X3 promoter.
Souslova et al. (1997) determined that the mouse P2rx3 gene contains 12 exons spanning approximately 40 kb. No significant similarities were found between the genomic organization of the mouse P2rx3 gene and genes encoding other ion channels.
By FISH analysis, Garcia-Guzman et al. (1997) mapped the P2RX3 gene to chromosome 11q12.
By FISH analysis, Souslova et al. (1997) mapped the mouse P2rx3 gene to chromosome 2p.
Kennedy and Leff (1995) commented that if ATP, and more specifically, P2X3 purinoceptors are involved in nociception, then the development of an antagonist selective for P2X3 could prove useful in pain relief. Lack of P2X3 in other tissues than sensory ganglia could afford a degree of specificity, leading to fewer side effects.
Finger et al. (2005) reported that ATP is a key neurotransmitter linking taste buds to sensory nerve fibers. Genetic elimination of ionotropic purinergic receptors (P2X2 and P2X3) eliminated taste responses in the taste nerves, although the nerves remained responsive to touch, temperature, and menthol. Similarly, P2x knockout mice showed greatly reduced behavioral responses to sweeteners, glutamate, and bitter substances. Finally, stimulation of taste buds in vitro evoked release of ATP. Thus, Finger et al. (2005) concluded that ATP fulfills the criteria for a neurotransmitter linking taste buds to the nervous system.
Grishin et al. (2010) isolated a novel peptide, which they termed purotoxin-1 (PT1), from the venom of the Central Asian wolf spider Geolycosa sp., that showed powerful and selective inhibitory action on P2X3 receptors. Although PT1 showed a small potentiating effect on the current generated by P2X3 receptors on rat dorsal root ganglia cells, it dramatically slowed decreased subsequent responses to ATP in desensitized receptors. Both effects were reversible. PT1 exerted its inhibitory effect by concentration-dependent prolongation of P2X3 desensitization removal. In animal models of inflammatory pain, PT1 showed potent antinociceptive properties.
Cockayne et al. (2000) and Souslova et al. (2000) generated mice deficient in P2X3 by targeted disruption. Cockayne et al. (2000) showed that mice deficient in P2X3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X3-null mice have reduced pain-related behavior in response to injection of ATP and formalin. Significantly, P2X3-null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localized P2X3 to nerve fibers innervating the urinary bladder of wildtype mice, and showed that loss of P2X3 does not alter sensory neuron innervation density. Thus, P2X3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder. Souslova et al. (2000) found that behavioral responses of P2X3-null mice to noxious mechanical and thermal stimuli were normal, although formalin-induced pain behavior was reduced. Souslova et al. (2000) also found that deletion of the P2X3 receptor caused enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application were normal, P2X3-null mice were unable to code the intensity of non-noxious 'warming' stimuli. In a commentary on the work of Cockayne et al. (2000) and Souslova et al. (2000), Cook and McCleskey (2000) remarked that initial analysis of these mice supports the idea that ATP contributes both to the pain resulting from tissue damage and to the pain resulting from a full bladder, and that, unexpectedly, the data also suggest that P2X3 receptors are involved in sensing warmth.
Chen, C.-C., Akopian, A. N., Sivilotti, L., Colquhoun, D., Burnstock, G., Wood, J. N. A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377: 428-430, 1995. [PubMed: 7566119] [Full Text: https://doi.org/10.1038/377428a0]
Cockayne, D. A., Hamilton, S. G., Zhu, Q.-M., Dunn, P. M., Zhong, Y., Novakovic, S., Malmberg, A. B., Cain, G., Berson, A., Kassotakis, L., Hedley, L., Lachnit, W. G., Burnstock, G., McMahon, S. B., Ford, A. P. D. W. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407: 1011-1015, 2000. [PubMed: 11069181] [Full Text: https://doi.org/10.1038/35039519]
Cook, S. P., McCleskey, E. W. ATP, pain and a full bladder. Nature 407: 951-952, 2000. [PubMed: 11069162] [Full Text: https://doi.org/10.1038/35039648]
Finger, T. E., Danilova, V., Barrows, J., Bartel, D. L., Vigers, A. J., Stone, L., Hellekant, G., Kinnamon, S. C. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310: 1495-1499, 2005. [PubMed: 16322458] [Full Text: https://doi.org/10.1126/science.1118435]
Garcia-Guzman, M., Stuhmer, W., Soto, F. Molecular characterization and pharmacological properties of the human P2X3 purinoceptor. Molec. Brain Res. 47: 59-66, 1997. [PubMed: 9221902] [Full Text: https://doi.org/10.1016/s0169-328x(97)00036-3]
Grishin, E. V., Savchenko, G. A., Vassilevski, A. A., Korolkova, Y. V., Boychuk, Y. A., Viatchenko-Karpinski, V. Y., Nadezhdin, K. D, Arseniev, A. S., Pluzhnikov, K. A., Kulyk, V. B., Voitenko, N. V., Krishtal, O. O. Novel peptide from spider venom inhibits P2X3 receptors and inflammatory pain. Ann. Neurol. 67: 680-683, 2010. [PubMed: 20437566] [Full Text: https://doi.org/10.1002/ana.21949]
Kennedy, C., Leff, P. Painful connection for ATP. Nature 377: 385-386, 1995. [PubMed: 7566110] [Full Text: https://doi.org/10.1038/377385a0]
Lewis, C., Neidhart, S., Holy, C., North, R. A., Buell, G., Surprenant, A. Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 377: 432-435, 1995. [PubMed: 7566120] [Full Text: https://doi.org/10.1038/377432a0]
Souslova, V., Cesare, P., Ding, Y., Akopian, A. N., Stanfa, L., Suzuki, R., Carpenter, K., Dickenson, A., Boyce, S., Hill, R., Nebenius-Oosthuizen, D., Smith, A. J. H., Kidd, E. J., Wood, J. N. Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407: 1015-1017, 2000. [PubMed: 11069182] [Full Text: https://doi.org/10.1038/35039526]
Souslova, V., Ravenall, S., Fox, M., Wells, D., Wood, J. N., Akopian, A. N. Structure and chromosomal mapping of the mouse P2X(3) gene. Gene 195: 101-111, 1997. [PubMed: 9300827] [Full Text: https://doi.org/10.1016/s0378-1119(97)00225-4]