Genomic Organization of Purinergic P2X Receptors

DOI: 10.4236/pp.2015.68036   PDF   HTML     3,013 Downloads   3,589 Views   Citations


Purinergic P2X receptors are a family of ligand-gated cationic channels activated by extracellular ATP. P2X subunit protein sequences are highly conserved between vertebrate species. However, they can generate a great diversity of coding splicing variants to fulfill several roles in mammalian physiology. Despite intensive research in P2X expression in both central and peripheral nervous system, there is little information about their homology, genomic structure and other key features that can help to develop selective drugs or regulatory strategies of pharmacological value which are lacking today. In order to obtain clues on mammalian P2X diversity, we have performed a bioinformatics analysis of the coding regions and introns of the seven P2X subunits present in human, simian, dog, mouse, rat and zebrafish. Here we report the arrangements of exon and intron sequences, considering its number, size, phase and placement; proposing some ideas about the gain and loss of exons and retention of introns. Taken together, these evidences show traits that can be used to gain insight into the evolutionary history of vertebrate P2X receptors and better understand the diversity of subunits coding the purinergic signaling in mammals.

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Loera-Valencia, R. , Jaramillo-Polanco, J. , Linan-Rico, A. , Nieto Pescador, M. , Jiménez Bremont, J. and Barajas-López, C. (2015) Genomic Organization of Purinergic P2X Receptors. Pharmacology & Pharmacy, 6, 341-362. doi: 10.4236/pp.2015.68036.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] North, R.A. (2002) Molecular physiology of P2X receptors. Physiological Reviews, 82 1013-1067.
[2] Cockayne, D.A., Dunn, P.M., Zhong, Y., Rong, W., Hamilton, S.G., Knight, G.E., Ruan, H.Z., Ma, B., Yip, P., Nunn, P., McMahon, S.B., Burnstock, G. and Ford, A.P. (2005) P2X2 Knockout Mice and P2X2/P2X3 Double Knockout Mice Reveal a Role for the P2X2 Receptor Subunit in Mediating Multiple Sensory Effects of ATP. The Journal of Physiology, 567, 621-639.
[3] Burnstock, G. (2007) Physiology and Pathophysiology of Purinergic Neurotransmission. Physiological Reviews, 87, 659-797.
[4] Coutinho-Silva, R., Knight, G.E. and Burnstock, G. (2005) Impairment of the Splenic Immune System in P2X2/P2X3 Knockout Mice. Immunobiology, 209, 661-668.
[5] Huang, L.C., Greenwood, D., Thorne, P.R. and Housley, G.D. (2005) Developmental Regulation of Neuron-Specific P2X3 Receptor Expression in the Rat Cochlea. Journal of Comparative Neurology, 484, 133-143.
[6] Torres, G.E., Egan, T.M. and Voigt, M.M. (1999) Hetero-Oligomeric Assembly of P2X Receptor Subunits. Specificities Exist with Regard to Possible Partners. The Journal of Biological Chemistry, 274, 6653-6659.
[7] Valera, S., Hussy, N., Evans, R.J., Adami, N., North, R.A., Surprenant, A. and Buell, G. (1994) A New Class of Ligand-Gated Ion Channel Defined by P2X Receptor for Extracellular ATP. Nature, 371, 516-519.
[8] Surprenant, A., Buell, G. and North, R.A. (1995) P2X Receptors Bring New Structure to Ligand-Gated Ion Channels. Trends in Neurosciences, 18, 224-229.
[9] Xiang, Z. and Burnstock, G. (2004) P2X2 and P2X3 Purinoceptors in the Rat Enteric Nervous System. Histochemistry and Cell Biology, 121, 169-179.
[10] Chen, C.C., Akopian, A.N., Sivilotti, L., Colquhoun, D., Burnstock, G. and Wood, J.N. (1995) A P2X Purinoceptor Expressed by a Subset of Sensory Neurons. Nature, 377, 428-431.
[11] Garcia-Guzman, M., Stuhmer, W. and Soto, F. (1997) Molecular Characterization and Pharmacological Properties of the Human P2X3 Purinoceptor. Molecular Brain Research, 47, 59-66.
[12] Ren, J., Bian, X., DeVries, M., Schnegelsberg, B., Cockayne, D.A., Ford, A.P. and Galligan, J.J. (2003) P2X2 Subunits Contribute to Fast Synaptic Excitation in Myenteric Neurons of the Mouse Small Intestine. The Journal of Physiology, 552, 809-821.
[13] Ruan, H.Z. and Burnstock, G. (2005) The Distribution of P2X5 Purinergic Receptors in the Enteric Nervous System of Mouse. Cell and Tissue Research, 319, 191-200.
[14] Fountain, S.J. and Burnstock, G. (2009) An Evolutionary History of P2X Receptors. Purinergic Signalling, 5, 269-272.
[15] Burnstock, G. and Verkhratsky, A. (2009) Evolutionary Origins of the Purinergic Signalling System. Acta Physiologica, 195, 415-447.
[16] Trams, E.G. (1981) On the Evolution of Neurochemical Transmission. Differentiation, 19, 125-133.
[17] Bavan, S., Straub, V.A., Blaxter, M.L. and Ennion, S.J. (2009) A P2X Receptor from the Tardigrade Species Hypsibius dujardini with Fast Kinetics and Sensitivity to Zinc and Copper. BMC Evolutionary Biology, 9, 17.
[18] Agboh, K.C., Webb, T.E., Evans, R.J. and Ennion, S.J. (2004) Functional Characterization of a P2X Receptor from Schistosoma mansoni. The Journal of Biological Chemistry, 279, 41650-41657.
[19] Muller, C.E. (2015) Medicinal Chemistry of P2X Receptors: Allosteric Modulators. Current Medicinal Chemistry, 22, 929-941.
[20] Rodriguez-Kessler, M., Delgado-Sanchez, P., Rodriguez-Kessler, G.T., Moriguchi, T. and Jimenez-Bremont, J.F. (2010) Genomic Organization of Plant Aminopropyl Transferases. Plant Physiology and Biochemistry, 48, 574-590.
[21] Li, M., Chang, T.H., Silberberg, S.D. and Swartz, K.J. (2008) Gating the Pore of P2X Receptor Channels. Nature Neuroscience, 11, 883-887.
[22] Castillo-Davis, C.I., Mekhedov, S.L., Hartl, D.L., Koonin, E.V. and Kondrashov, F.A. (2002) Selection for Short Introns in Highly Expressed Genes. Nature Genetics, 31, 415-418.
[23] Eisenberg, E. and Levanon, E.Y. (2003) Human Housekeeping Genes Are Compact. Trends in Genetics, 19, 362-365.
[24] Rao, Y.S., Wang, Z.F., Chai, X.W., Wu, G.Z., Zhou, M., Nie, Q.H. and Zhang, X.Q. (2010) Selection for the Compactness of Highly Expressed Genes in Gallus gallus. Biology Direct, 5, 35.
[25] Linan-Rico, A., Jaramillo-Polanco, J., Espinosa-Luna, R., Jimenez-Bremont, J.F., Linan-Rico, L., Montano, L.M. and Barajas-Lopez, C. (2012) Retention of a New-Defined Intron Changes Pharmacology and Kinetics of the Full-Length P2X2 Receptor Found in Myenteric Neurons of the Guinea Pig. Neuropharmacology, 63, 394-404.
[26] Brosenitsch, T.A., Adachi, T., Lipski, J., Housley, G.D. and Funk, G.D. (2005) Developmental Downregulation of P2X3 Receptors in Motoneurons of the Compact Formation of the Nucleus Ambiguus. European Journal of Neuroscience, 22, 809-824.
[27] Ruan, H.Z., Moules, E. and Burnstock, G. (2004) Changes in P2X3 Purinoceptors in Sensory Ganglia of the Mouse during Embryonic and Postnatal Development. Histochemistry and Cell Biology, 122, 539-551.
[28] Xiang, Z. and Burnstock, G. (2004) Development of Nerves Expressing P2X3 Receptors in the Myenteric Plexus of Rat Stomach. Histochemistry and Cell Biology, 122, 111-119.
[29] Loera-Valencia, R., Jimenez-Vargas, N.N., Villalobos, E.C., Juarez, E.H., Lomas-Ramos, T.L., Espinosa-Luna, R., Montano, L.M., Huizinga, J.D. and Barajas-Lopez, C. (2014) Expression of P2X3 and P2X5 Myenteric Receptors Varies during the Intestinal Postnatal Development in the Guinea Pig. Cellular and Molecular Neurobiology, 34, 727-736.
[30] Majewski, J. and Ott, J. (2002) Distribution and Characterization of Regulatory Elements in the Human Genome. Genome Research, 12, 1827-1836.
[31] Kalari, K.R., Casavant, M., Bair, T.B., Keen, H.L., Comeron, J.M., Casavant, T.L. and Scheetz, T.E. (2006) First Exons and Introns—A Survey of GC Content and Gene Structure in the Human Genome. In Silico Biology, 6, 237-242.
[32] Zhu, L., Zhang, Y., Zhang, W., Yang, S., Chen, J.Q. and Tian, D. (2009) Patterns of Exon-Intron Architecture Variation of Genes in Eukaryotic Genomes. BMC Genomics, 10, 47.
[33] Egan, T.M., Cox, J.A. and Voigt, M.M. (2000) Molecular Cloning and Functional Characterization of the Zebrafish ATP-Gated Ionotropic Receptor P2X3 Subunit. FEBS Letters, 475, 287-290.
[34] Diaz-Hernandez, M., Cox, J.A., Migita, K., Haines, W., Egan, T.M. and Voigt, M.M. (2002) Cloning and Characterization of Two Novel Zebrafish P2X Receptor Subunits. Biochemical and Biophysical Research Communications, 295, 849-853.
[35] Kucenas, S., Li, Z., Cox, J.A., Egan, T.M. and Voigt, M.M. (2003) Molecular Characterization of the Zebrafish P2X Receptor Subunit Gene Family. Neuroscience, 121, 935-945.
[36] Babenko, V.N., Rogozin, I.B., Mekhedov, S.L. and Koonin, E.V. (2004) Prevalence of Intron Gain Over Intron Loss in the Evolution of Paralogous Gene Families. Nucleic Acids Research, 32, 3724-3733.
[37] Carmel, L., Rogozin, I.B., Wolf, Y.I. and Koonin, E.V. (2007) Patterns of Intron Gain and Conservation in Eukaryotic Genes. BMC Evolutionary Biology, 7, 192.
[38] Rogozin, I.B., Wolf, Y.I., Sorokin, A.V., Mirkin, B.G. and Koonin, E.V. (2003) Remarkable Interkingdom Conservation of Intron Positions and Massive, Lineage-Specific Intron Loss and Gain in Eukaryotic Evolution. Current Biology, 13, 1512-1517.
[39] Okamura, Y., Nishino, A., Murata, Y., Nakajo, K., Iwasaki, H., Ohtsuka, Y., Tanaka-Kunishima, M., Takahashi, N., Hara, Y., Yoshida, T., Nishida, M., Okado, H., Watari, H., Meinertzhagen, I.A., Satoh, N., Takahashi, K., Satou, Y., Okada, Y. and Mori, Y. (2005) Comprehensive Analysis of the Ascidian Genome Reveals Novel Insights into the Molecular Evolution of Ion Channel Genes. Physiological Genomics, 22, 269-282.
[40] Amores, A., Force, A., Yan, Y.L., Joly, L., Amemiya, C., Fritz, A., Ho, R.K., Langeland, J., Prince, V., Wang, Y.L., Westerfield, M., Ekker, M. and Postlethwait, J.H. (1998) Zebrafish Hox Clusters and Vertebrate Genome Evolution. Science, 282, 1711-1714.
[41] Postlethwait, J.H., Yan, Y.L., Gates, M.A., Horne, S., Amores, A., Brownlie, A., Donovan, A., Egan, E.S., Force, A., Gong, Z., Goutel, C., Fritz, A., Kelsh, R., Knapik, E., Liao, E., Paw, B., Ransom, D., Singer, A., Thomson, M., Abduljabbar, T.S., Yelick, P., Beier, D., Joly, J.S., Larhammar, D., Rosa, F., Westerfield, M., Zon, L.I., Johnson, S.L. and Talbot, W.S. (1998) Vertebrate Genome Evolution and the Zebrafish Gene Map. Nature Genetics, 18, 345-349.
[42] Woods, I.G., Kelly, P.D., Chu, F., Ngo-Hazelett, P., Yan, Y.L., Huang, H., Postlethwait, J.H. and Talbot, W.S. (2000) A Comparative Map of the Zebrafish Genome. Genome Research, 10, 1903-1914.
[43] Taylor, J.S., Braasch, I., Frickey, T., Meyer, A. and Van de Peer, Y. (2003) Genome Duplication, a Trait Shared by 22000 Species of Ray-Finned Fish. Genome Research, 13, 382-390.
[44] Woods, I.G., Wilson, C., Friedlander, B., Chang, P., Reyes, D.K., Nix, R., Kelly, P.D., Chu, F., Postlethwait, J.H. and Talbot, W.S. (2005) The Zebrafish Gene Map Defines Ancestral Vertebrate Chromosomes. Genome Research, 15, 1307-1314.
[45] Ruvinsky, A. and Watson, C. (2007) Intron Phase Patterns in Genes: Preservation and Evolutionary Changes. The Open Evolution Journal, 1, 1-14.
[46] Fedorov, A., Suboch, G., Bujakov, M. and Fedorova, L. (1992) Analysis of Nonuniformity in Intron Phase Distribution. Nucleic Acids Research, 20, 2553-2557.
[47] Artamonova, I.I. and Gelfand, M.S. (2007) Comparative Genomics and Evolution of Alternative Splicing: The Pessimists’ Science. Chemical Reviews, 107, 3407-3430.
[48] Ruvinsky, A. and Ward, W. (2006) A Gradient in the Distribution of Introns in Eukaryotic Genes. Journal of Molecular Evolution, 63, 136-141.
[49] Fedorov, A., Roy, S., Fedorova, L. and Gilbert, W. (2003) Mystery of Intron Gain. Genome Research, 13, 2236-2241.
[50] Roy, S.W. (2004) The Origin of Recent Introns: Transposons? Genome Biology, 5, 251.
[51] Ogino, K., Tsuneki, K. and Furuya, H. (2010) Unique Genome of Dicyemid Mesozoan: Highly Shortened Spliceosomal Introns in Conservative Exon/Intron Structure. Gene, 449, 70-76.
[52] Collins, L. and Penny, D. (2006) Investigating the Intron Recognition Mechanism in Eukaryotes. Molecular Biology and Evolution, 23, 901-910.
[53] Bo, X., Schoepfer, R. and Burnstock, G. (2000) Molecular Cloning and Characterization of a Novel ATP P2X Receptor Subtype from Embryonic Chick Skeletal Muscle. The Journal of Biological Chemistry, 275, 14401-14407.
[54] Fountain, S.J., Cao, L., Young, M.T. and North, R.A. (2008) Permeation Properties of a P2X Receptor in the Green Algae Ostreococcus tauri. The Journal of Biological Chemistry, 283, 15122-15126.
[55] Fountain, S.J., Parkinson, K., Young, M.T., Cao, L., Thompson, C.R. and North, R.A. (2007) An Intracellular P2X Receptor Required for Osmoregulation in Dictyostelium discoideum. Nature, 448, 200-203.
[56] Dubyak, G.R. (2007) Go It Alone No More—P2X7 Joins the Society of Heteromeric ATP-Gated Receptor Channels. Molecular Pharmacology, 72, 1402-1405.
[57] Bernier, L.P. (2012) Purinergic Regulation of Inflammasome Activation after Central Nervous System Injury. The Journal of General Physiology, 140, 571-575.
[58] Kaan, T.K., Yip, P.K., Patel, S., Davies, M., Marchand, F., Cockayne, D.A., Nunn, P.A., Dickenson, A.H., Ford, A.P., Zhong, Y., Malcangio, M. and McMahon, S.B. (2010) Systemic Blockade of P2X3 and P2X2/3 Receptors Attenuates Bone Cancer Pain Behaviour in Rats. Brain, 133, 2549-2564.
[59] Sperlagh, B. and Illes, P. (2014) P2X7 Receptor: An Emerging Target in Central Nervous System Diseases. Trends in Pharmacological Sciences, 35, 537-547.
[60] Tsuchihara, T., Ogata, S., Nemoto, K., Okabayashi, T., Nakanishi, K., Kato, N., Morishita, R., Kaneda, Y., Uenoyama, M., Suzuki, S., Amako, M., Kawai, T. and Arino, H. (2009) Nonviral Retrograde Gene Transfer of Human Hepatocyte Growth Factor Improves Neuropathic Pain-Related Phenomena in Rats. Molecular Therapy, 17, 42-50.

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