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Review
. 2012 Sep;8(3):375-417.
doi: 10.1007/s11302-012-9314-7. Epub 2012 May 1.

Molecular and functional properties of P2X receptors--recent progress and persisting challenges

Karina Kaczmarek-Hájek  1 , Eva Lörinczi, Ralf Hausmann, Annette Nicke
Affiliations
Review

Molecular and functional properties of P2X receptors--recent progress and persisting challenges

Karina Kaczmarek-Hájek et al. Purinergic Signal. 2012 Sep.

Abstract

ATP-gated P2X receptors are trimeric ion channels that assemble as homo- or heteromers from seven cloned subunits. Transcripts and/or proteins of P2X subunits have been found in most, if not all, mammalian tissues and are being discovered in an increasing number of non-vertebrates. Both the first crystal structure of a P2X receptor and the generation of knockout (KO) mice for five of the seven cloned subtypes greatly advanced our understanding of their molecular and physiological function and their validation as drug targets. This review summarizes the current understanding of the structure and function of P2X receptors and gives an update on recent developments in the search for P2X subtype-selective ligands. It also provides an overview about the current knowledge of the regulation and modulation of P2X receptors on the cellular level and finally on their physiological roles as inferred from studies on KO mice.

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Figures

Fig. 1
Fig. 1
Evolutionary relationship of P2X receptors and common model organisms. Left panel: Unrooted neighbor-joining phylogeny of identified P2X protein sequences. The tree was constructed using the MEGA program (http://www.megasoftware.net/). The scale bar indicates the genetic distance in percent sequence divergence. Right panel: A phylogenetic tree showing the relationship between organisms in which P2X receptors are present and common model organisms in which P2X receptors have not been identified (indicated by question mark). The tree was created by hand and edited using the program Dendroscope (http://ab.inf.uni-tuebingen.de/software/dendroscope/) based on the information given in King et al. [35]. The following P2X receptor sequences were used: D. discoideum (XP_645378.1, XP_643830.2, XP_643831.1, XP_636768.1, XP_636957.2), M. brevicollis (EDQ92249.1), S. mansoni (CAH04147.1), H. dujardini (ACL14328.1), B. microplus (ADO64254.1), A. californica (AAR28669.1), D. rerio (NP_945333.1, NP_945334.1, NP_571698.1, NP_945337.2, AAH42317.1, AAI62598.1, NP_945336.1, NP_945335.1), M. musculus (AAF68968.1, AAK95327.2, AAH23089.1, AAC95601.1, AAK49936.1, NP_035158.2, NP_035157.2, AAI62774.1), H. sapiens (NP_002549.1, NP_733782.1, NP_002550.2, NP_002551.2, NP_002552.2, NP_005437.2, NP_002553.3), O. tauri (CAL54489.1). We thank Steve Ennion for providing the sequence of L. stagnalis and Henrik Krehenwinkel for phylogenetic analysis
Fig. 2
Fig. 2
Homology model of the homomeric P2X2 receptor. The homotrimeric rP2X2 receptor structure is shown from the side, i.e., parallel to the membrane plane. Two subunits are shown as pink or gray sticks; one subunit is highlighted as ribbon representation with depiction of α-helices, β-sheets, and coil regions. The dolphin-like shape of this single subunit [48] (body, blue; fluke, green; head, pink; dorsal fin, orange; right flipper, red; left flipper, yellow) is emphasized by an overlay of a grey dolphin cartoon. The arrowhead indicates one of the three possible ATP binding pockets. The rP2X2 receptor homology model based on the X-ray structure of the zP2X4.1 receptor was generated using the MOE2008.10 software. For further details, see [93]. The figure was generated and kindly provided by Achim Kless, Grünenthal GmbH, Global Drug Discovery
Fig. 3
Fig. 3
Proposed binding of the antagonist NF770 to the P2X2 receptor. The suramin derivative NF770 (7,7-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methylphenylene)carbonylimino))bis(1-methoxy-naphthalene-3,6-disulfonic acid) tetrasodium salt)) is shown within the rP2X2 receptor binding pocket. Selected residues of the rP2X2 receptor binding site are shown as pink sticks, side chains of Gly72, Arg290, Glu167 and Lys308 are shown as ball and stick or space filling. NF770 is directed by a Gly72-sulfonate group (yellow/brown sticks) interaction to orient spatially in a way that the methoxy group oxygen (brown stick) comes into close apposition to Arg290. This way, a hydrogen bond can form that is a key determinant of the interaction of NF770 with the rP2X2 receptor. The close distance of 2.13 Å between the methoxy group and Arg290 (yellow bar) appears to account for the strong binding. The rP2X2 receptor homology model based on the X-ray structure of zP2X4.1 was generated by MOE2008.10. The receptor model was kept rigid during the docking computation, whereas the NF770 was allowed to remain flexible. For further details, see Wolf et al. [93]. The figure was generated and kindly provided by Achim Kless, Grünenthal GmbH, Global Drug Discovery
Fig. 4
Fig. 4
Summary of published P2X receptor−/− mice and the targeting strategies used for their generation. Location of TM encoding exons are only shown for the P2X7 receptor, but, due to the strong conservation of exon-intron boundaries in P2X receptor encoding genes, can be transferred to the other subtypes. The figure also illustrates alternative exons (1´and 13b/c) identified in the rodent P2X7 gene [300, 525] and explains how the P2X7K splice variant derived from exon 1´ can escape the gene deletion strategy used in one of the available P2X7−/− mouse lines. Note that all cassettes indicated with lacZ represent actually lacZ-NeoR cassettes
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