Alternative titles; symbols
HGNC Approved Gene Symbol: P2RX2
Cytogenetic location: 12q24.33 Genomic coordinates (GRCh38): 12:132,618,776-132,622,388 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.33 | Deafness, autosomal dominant 41 | 608224 | Autosomal dominant | 3 |
The P2RX2 gene encodes the P2X2 receptor, which assembles as a trimer to form a ligand-gated ion channel gated by extracellular ATP. P2X2 receptors mediate a variety of cellular responses, including excitatory postsynaptic responses in sensory neurons (summary by Yan et al., 2013).
The rat P2X2 gene was cloned by Brake et al. (1994). Lewis et al. (1995) cloned the rat gene from dorsal root ganglia and demonstrated that coexpression of P2X3 (600843) with P2X2, but not other combinations, yielded ATP-activated currents that closely resembled those in sensory neurons. In general, their results indicated that ATP-gated channels of sensory neurons formed by a specific heteropolymerization of P2X receptor subunits.
Lynch et al. (1999) cloned and characterized the human P2X2 gene. The full-length cDNA encoded a predicted 471-amino acid protein that was 68% identical to rat P2X2. Northern blot analysis detected a major mRNA species of approximately 2.4 kb in pancreas; extended exposure detected faint bands of the same size in heart and brain. Two of 4 isolated cDNAs representing splice variants expressed in Xenopus oocytes encoded functional ion channels.
Using RT-PCR analysis, Housley et al. (1999) found that 2 P2x2 splice variants were expressed in guinea pig cochlea. Variant-1 was expressed in sensory epithelium of the organ of Corti, and variant-2, which encodes a desensitizing isoform, was expressed by primary auditory neurons. Immunohistochemical analysis detected highest P2x2 expression in hair cell stereocilia facing the endolymph, in Deiters cells within the perilymphatic compartment, and in afferent neurons of the spiral ganglion. Immunoelectron microscopy localized P2x2 to postsynaptic junctions at both inner and outer hair cells.
Using immunofluorescence assays, Chen et al. (2021) showed that P2rx2 was expressed in the plasma membrane, Golgi apparatus, and mitochondria of mouse tail fibroblasts.
Transmitter-gated cation channels are detectors of excitatory chemical signals at synapses in the nervous system. Khakh et al. (2000) showed that structurally distinct alpha-3 (118503)-beta-4 (118509) nicotinic and P2X(2) channels influence each other when coactivated. The activation of one channel type affects distinct kinetic and conductance states of the other, and coactivation results in nonadditive responses owing to inhibition of both channel types. State-dependent inhibition of nicotinic channels was revealed most clearly with mutant P2X(2) channels, and inhibition was decreased at lower densities of channel expression. In synaptically coupled myenteric neurons, nicotinic fast excitatory postsynaptic currents were occluded during activation of endogenously coexpressed P2X channels. Khakh et al. (2000) concluded that their data provide a molecular basis and a synaptic context for cross-inhibition between transmitter-gated channels.
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.
Using isolated guinea pig outer hair cells (OHCs), Yu and Zhao (2008) found that ATP-activated P2rx2 influenced OHC electromotility, a stimulus-induced change in hair cell length that functions as an amplifier to determine hearing sensitivity and frequency selectivity. ATP, but not UTP, reduced OHC electromotility-associated nonlinear capacitance and shifted its voltage dependency toward depolarization. Pharmacologic blockade of P2rx2 activation or removal of extracellular but not intracellular Ca(2+) abolished the ATP effect. Yu and Zhao (2008) concluded that ATP activates P2RX2 channels to modify OHC electromotility and that extracellular Ca(2+) is required for the effect.
In neonatal rat tissue, Yan et al. (2013) found that P2rx2 localized to the apical plasma membranes of auditory hair cells of the organ of Corti, including the stereociliary bundles. The pattern of expression within cell bodies indicated that P2x2 receptors are synthesized and compartmentalized in the endoplasmic reticulum and Golgi complex. This distribution was consistent with the localization of P2rx2 to the endolymphatic surface of the sensory hair cells and other epithelial cells of the cochlear partition.
Efferent feedback to the cochlea rapidly adapts to intense sound, beginning well below safe upper hearing limits, and induces a temporary threshold shift that protects the cochlea from subsequent overstimulation. Both the endocochlear potential and the hair-cell membrane potential are reduced by activation of purinergic signaling. By comparing auditory brainstem responses of wildtype and P2rx2-knockout mice to increased duration and intensity of noise, Housley et al. (2013) found that P2rx2 channels were necessary for development of the temporary threshold shift. Activation of P2rx2 channels by elevated sound intensity reduced sound transduction and synaptic transmission from hair cells.
Lynch et al. (1999) determined that the human P2RX2 gene contains 11 exons.
Gross (2014) mapped the P2RX2 gene to chromosome 12q24.33 based on an alignment of the P2RX2 sequence (GenBank AF109387) with the genomic sequence (GRCh38).
Chen et al. (2021) stated that the P2rx2 gene maps to mouse chromosome 5.
In affected members of 2 unrelated Chinese families with autosomal dominant deafness-41 (DFNA41; 608224), Yan et al. (2013) identified a heterozygous missense mutation in the P2RX2 gene (V60L; 600844.0001). The mutation in the first family was found by whole-exome sequencing; the second family was 1 of 65 families in whom the P2RX2 gene was sequenced. In vitro functional expression studies showed that the V60L mutation caused a loss of channel function with a loss of inward current and macropore permeability. All mutation carriers developed progressive hearing loss in the second decade that ultimately affected all frequencies. Exposure to noise caused more severe hearing loss at high frequencies. The findings provided a link between P2X2 receptor signaling in the cochlea and protection from noise and progressive hearing loss.
Faletra et al. (2014) identified a heterozygous missense mutation in the P2RX2 gene (G353R; 600844.0002) in affected members of a large Italian family with DFNA41, confirming the findings of Yan et al. (2013) that mutations in this gene can cause progressive hearing loss.
Yan et al. (2013) found that P2rx2-null mice developed progressive hearing loss at about 19 to 23 weeks of age in the absence of noise exposure. At 17 months of age, mutant mice had significantly more severe age-related hearing loss compared to wildtype mice, and the hearing loss was due to loss of outer hair cell function in the mid-basal region of the cochlea. Histologic analysis of older mutant mice showed deterioration of the organ of Corti, loss of hair cells, loss of sensory epithelium, and loss of spiral ganglion neurons within the Rosenthal canal. Exposure to noise impaired hearing in both wildtype and mutant mice, but mutant mice showed more severe hearing loss at higher frequencies compared to wildtype mice after noise exposure.
Using auditory brainstem responses, Housley et al. (2013) found that P2rx2 -/- mice showed normal hearing function in the absence of noise and at moderate noise intensity. However, P2rx2 -/- mice were unable to mount a protective temporary threshold shift in response to elevated noise intensity and duration. Consequently, P2rx2 -/- mice were vulnerable to noise-induced hearing loss with acoustic overstimulation. P2rx2 -/- mice lacked ATP-gated conductance across the cochlea, including loss of ATP-gated inward current in hair cells. Histologic examination revealed normal numbers of inner and outer hair cells in P2rx2 -/- mice, but these hairs showed damaged spiral ganglion synapse structure and reduced number of ribbon synapses at the inner hair cell, consistent with neural rather than hair cell injury.
Chen et al. (2021) were unable to obtain knockin mice homozygous for a val61-to-lue (V61L) mutation in P2rx2, corresponding to the human V60L mutation (600844.0001) associated with deafness (DFNA41; 608224), likely due to male sterility. Heterozygous V61L knockin mice exhibited normal general characteristics and activity level, and the V61L mutation did not alter molecular mass, subcellular localization, or expression pattern of the P2rx2 protein. However, cells from the knockin mice grew more slowly than wildtype. Mice heterozygous for V61L displayed early-onset and progressive hearing loss, recapitulating the human phenotype. Moreover, mutant mice had vestibular dysfunction and increased sensitivity to pain. V61L mutant mice had normal cochlear structure, but they exhibited aberrant distribution of synaptic ribbons and degeneration of inner hair cells without hair cell loss.
In affected members of a large Chinese family with autosomal dominant deafness-41 (DFNA41; 608224), originally reported by Blanton et al. (2002), Yan et al. (2013) identified a heterozygous c.178G-T transversion in the P2RX2 gene, resulting in a val60-to-leu (V60L) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing of the linkage candidate region on chromosome 12q24 and confirmed by Sanger sequencing, segregated with the disorder in the family. Sequencing of the P2RX2 coding region in 65 additional families with autosomal dominant hearing loss identified 1 other Chinese family with the same mutation. The mutation was not found in 7,000 controls, including 500 persons of Chinese ancestry. Mutation carriers had onset of progressive hearing loss in their second decade, with severe loss affecting all frequencies by age 20 years. Those who had a history of occupational noise exposure as young adults had more severe hearing loss at high frequencies (2,000-8,000 Hz range) compared to those with no history of noise exposure. The mutant protein localized properly to the apical membrane of hair cells in the organ of Corti of neonatal rats. However, patch-clamp recording in HEK293 cells transfected with the mutation showed that the mutant channel had no response to ATP, and the mutant channels were impermeable to cationic dyes. Expression of the mutant protein with wildtype proteins reduced cationic permeability by 60% compared to wildtype alone.
In affected members of a large Italian family with DFNA41 (608224), Faletra et al. (2014) identified a heterozygous c.1057G-C transversion in exon 10 of the P2RX2 gene, resulting in a gly353-to-arg (G353R) substitution at a highly conserved residue. The mutation segregated with the phenotype in the family and was not found in 500 ethnically matched chromosomes. Three-dimensional molecular modeling showed that the substitution occurs at the C terminus of the TM2 helix, embedded near or within the lipid channel bilayer, likely causing destabilization or structural distortion of the channel.
Blanton, S. H., Liang, C. Y., Cai, M. W., Pandya, A., Du, L. L., Landa, B., Mummalanni, S., Li, K. S., Chen, Z. Y., Qin, X. N., Liu, Y. F., Balkany, T., Nance, W. E., Liu, X. Z. A novel locus for autosomal dominant non-syndromic deafness (DFNA41) maps to chromosome 12q24-qter. J. Med. Genet. 39: 567-570, 2002. [PubMed: 12161595] [Full Text: https://doi.org/10.1136/jmg.39.8.567]
Brake, A. J., Wagenbach, M. J., Julius, D. New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor. Nature 371: 519-523, 1994. [PubMed: 7523952] [Full Text: https://doi.org/10.1038/371519a0]
Chen, X., Abad, C., Chen, Z. Y., Young, J. I., Gurumurthy, C. B., Walz, K., Liu, X. Z. Generation and characterization of a P2rx2 V60L mouse model for DFNA41. Hum. Molec. Genet. 30: 985-995, 2021. [PubMed: 33791800] [Full Text: https://doi.org/10.1093/hmg/ddab077]
Faletra, F., Girotto, G., D'Adamo, A. P., Vozzi, D., Morgan, A., Gasparini, P. A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss. Gene 534: 236-239, 2014. [PubMed: 24211385] [Full Text: https://doi.org/10.1016/j.gene.2013.10.052]
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]
Gross, M. B. Personal Communication. Baltimore, Md. 10/22/2014.
Housley, G. D., Kanjhan, R., Raybould, N. P., Greenwood, D., Salih, S. G., Jarlebark, L., Burton, L. D., Setz, V. C. M., Cannell, M. B., Soeller, C., Christie, D. L., Usami, S., Matsubara, A., Yoshie, H., Ryan, A. F., Thorne, P. R. Expression of the P2X(2) receptor subunit of the ATP-gated ion channel in the cochlea: implications for sound transduction and auditory neurotransmission. J. Neurosci. 19: 8377-8388, 1999. [PubMed: 10493739] [Full Text: https://doi.org/10.1523/JNEUROSCI.19-19-08377.1999]
Housley, G. D., Morton-Jones, R., Vlajkovic, S. M., Telang, R. S., Paramananthasivam, V., Tadros, S. F., Wong, A. C. Y., Froud, K. E., Cederholm, J. M. E., Sivakumaran, Y., Snguanwongchai, P., Khakh, B. S., Cockayne, D. A., Thorne, P. R., Ryan, A. F. ATP-gated ion channels mediate adaptation to elevated sound levels. Proc. Nat. Acad. Sci. 110: 7494-7499, 2013. [PubMed: 23592720] [Full Text: https://doi.org/10.1073/pnas.1222295110]
Khakh, B. S., Zhou, X., Sydes, J., Galligan, J. J., Lester, H. A. State-dependent cross-inhibition between transmitter-gated cation channels. Nature 406: 405-410, 2000. [PubMed: 10935636] [Full Text: https://doi.org/10.1038/35019066]
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]
Lynch, K. J., Touma, E., Niforatos, W., Kage, K. L., Burgard, E. C., van Biesen, T., Kowaluk, E. A., Jarvis, M. F. Molecular and functional characterization of human P2X(2) receptors. Molec. Pharm. 56: 1171-1181, 1999. [PubMed: 10570044] [Full Text: https://doi.org/10.1124/mol.56.6.1171]
Yan, D., Zhu, Y., Walsh, T., Xie, D., Yuan, H., Sirmaci, A., Fujikawa, T., Wong, A. C. Y., Loh, T. L., Du, L., Grati, M., Vlajkovic, S. M., and 10 others. Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc. Nat. Acad. Sci. 110: 2228-2233, 2013. [PubMed: 23345450] [Full Text: https://doi.org/10.1073/pnas.1222285110]
Yu, N., Zhao, H.-B. ATP activates P2x receptors and requires extracellular Ca(++) participation to modify outer hair cell nonlinear capacitance. Pflugers Arch. 457: 453-461, 2008. [PubMed: 18491132] [Full Text: https://doi.org/10.1007/s00424-008-0522-5]