A Functional P2X7 Splice Variant with an Alternative Transmembrane Domain 1 Escapes Gene Inactivation in P2X7 Knock-out Mice

Nicke, Annette; Kuan, Yung-Hui; Masin, Marianela; Rettinger, Jürgen; Marquez-Klaka, Benjamin; Bender, Olaf; Górecki, Dariusz C.; Murrell‐Lagnado, Ruth D.; Soto, Florentina

doi:10.1074/jbc.m109.033134

Cited by 172 publications

(244 citation statements)

References 49 publications

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“…This receptor is still functional in the knockout mice used in this study (35), and expression patterns show this isoform is enriched in cells in the thymus and spleen of WT and P2X 7 R 2/2 mice, suggesting that it is involved in a specific function in these tissues (36). Therefore, this may account for the increased numbers of CD3 + T cells that we observed in the P2X 7 R 2/2 animals.…”

Section: Discussionmentioning

confidence: 66%

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

Keating

Pelegrı́n²,

Martínez³

et al. 2011

The Journal of Immunology

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The ATP-gated P2X7 receptor (P2X7R) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL-1β processing and release. Trichinella spiralis-infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome. In this study, we used P2X7R knockout mice (P2X7R−/−) to investigate the role of P2X7R activation in the in vivo production of IL-1β and the development of postinflammatory visceral hypersensitivity in the T. spiralis-infected mouse. During acute nematode infection, IL-1β–containing cells and P2X7R expression were increased in the jejunum of wild-type (WT) mice. Peritoneal and serum IL-1β levels were also increased, which was indicative of elevated IL-1β release. However, in the P2X7R−/− animals, we found that infection had no effect upon intracellular, plasma, or peritoneal IL-1β levels. Conversely, infection augmented peritoneal TNF-α levels in both WT and P2X7R−/− animals. Infection was also associated with a P2X7R-dependent increase in extracellular peritoneal lactate dehydrogenase, and it triggered immunological changes in both strains. Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X7R−/− animals. Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli; however, this did not develop in postinfected P2X7R−/− animals. Therefore, our results demonstrated that P2X7Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity.

show abstract

Section: Discussionmentioning

confidence: 66%

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

Keating

Pelegrı́n²,

Martínez³

et al. 2011

The Journal of Immunology

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“…A similar difference was found for the mouse P2X7aR and P2X7kR (P NMDG / P Na 0.05 Ϯ 0.01, n ϭ 11; and 0.40 Ϯ 0.03, n ϭ 11). The disparity in baseline permeability to the large (4.5 Å) polyatomic NMDG ϩ supports the suggestion that the selectivity filters of the P2X7a and P2X7k splice variants adopt different initial open state conformations with dissimilar cation permeabilities (57). To explore this hypothesis further, we sought to determine whether the contribution of the physiologically relevant divalent cation, Ca 2ϩ , to whole cell current also differed.…”

Section: Resultsmentioning

confidence: 89%

“…Ten splice variants (P2X7bR-P2X7kR) have been identified from a range of species since the initial molecular cloning of the first P2X7R from rat (now called rat P2X7aR) (6). Only two of these (human P2X7bR and murine P2X7kRs) form functional homomeric receptors (56,57). We discovered that mouse and rat splice variants with identical pore-lining sequences show significantly different Pf %, suggesting that domains that lie outside of the channel pore regulate the Ca 2ϩ component of the ATP-gated current.…”

Section: Atp-gated P2x7 Receptors Are Prominently Expressed In Inflammentioning

confidence: 99%

Quantifying Ca2+ Current and Permeability in ATP-gated P2X7 Receptors

Liang¹,

Samways²,

Wolf³

et al. 2015

Journal of Biological Chemistry

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Background: Ca 2ϩ triggers many of the actions of extracellular ATP. Results: We measured the Ca 2ϩ component of the ATP-gated non-selective cation current of P2X7 receptors. Conclusion: Ca 2ϩ flux varied with the species of origin, the splice variant, and the agonist concentration. Significance: Our results suggest that domains that lie outside of the pore regulate the Ca 2ϩ flux of P2X7 receptors.

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“…A separate study by Gartland et al (Gartland et al, 2003b) reported no differences in bone mineral density or trabecular bone but an increase in cortical bone was observed. It was subsequently reported that the knockout model used by Gartland et al expressed a P2X7 splice variant in some tissues (Nicke et al, 2009); therefore the results from this model should be interpreted with caution. Further complicating the analysis of this knockout mouse model, a recent study found that the genetic background strongly influenced the bone phenotype (Syberg et al, 2012b).…”

Section: P2x Receptors and Osteoblastsmentioning

confidence: 99%

The role of purinergic signalling in the musculoskeletal system

Orriss

2015

Autonomic Neuroscience

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A Functional P2X7 Splice Variant with an Alternative Transmembrane Domain 1 Escapes Gene Inactivation in P2X7 Knock-out Mice

Cited by 172 publications

References 49 publications

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

Quantifying Ca2+ Current and Permeability in ATP-gated P2X7 Receptors

The role of purinergic signalling in the musculoskeletal system

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