Cutting Edge: The Nucleotide Receptor P2X7 Contains Multiple Protein- and Lipid-Interaction Motifs Including a Potential Binding Site for Bacterial Lipopolysaccharide

Denlinger, Loren C.; Fisette, Philip L.; Sommer, Julie A.; Watters, Jyoti J.; Prabhu, Usha; Dubyak, George R.; Proctor, Richard A.; Bertics, Paul J.

doi:10.4049/jimmunol.167.4.1871

Cited by 172 publications

(184 citation statements)

References 41 publications

(52 reference statements)

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“…The allelic association findings with rs2230912 (P2RX7-E13A) are interesting because the G allele of this SNP alters a highly conserved glutamine residue in an SH-3 domain to arginine. The residue is located in an intracellular domain of P2RX7 36 and may have effects on P2RX7-mediated signalling. Replication of the association between allele G at rs2230912 with affective disorder in further samples may require larger sample sizes than employed so far if the disease allele G has an odds ratio of p1.3.…”

Section: Discussionmentioning

confidence: 99%

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

et al. 2008

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Three linkage studies of bipolar disorder have implicated chromosome 12q24.3 with lod scores of over 3.0 and several other linkage studies have found lods between 2 and 3. Fine mapping within the original chromosomal linkage regions has identified several loci that show association with bipolar disorder. One of these is the P2RX7 gene encoding a central nervous system-expressed purinergic receptor. A non-synonymous single nucleotide polymorphism, rs2230912 (P2RX7-E13A, G allele) and a microsatellite marker NBG6 were both previously found to be associated with bipolar disorder (P = 0.00071 and 0.008, respectively). rs2230912 has also been found to show association with unipolar depression. The effect of the polymorphism is non-conservative and results in a glutamine to arginine change (Gln460Arg), which is likely to affect P2RX7 dimerization and protein-protein interactions. We have confirmed the allelic associations between bipolar disorder and the markers rs2230912 (P2RX7-E13A, G allele, P = 0.043) and NBG6 (P = 0.010) in a London-based sample of 604 bipolar cases and 560 controls. When we combined these data with the published case-control studies of P2RX7 and mood disorder (3586 individuals) the association between rs2230912 (Gln460Arg) and affective disorders became more robust (P = 0.002). The increase in Gln460Arg was confined to heterozygotes rather than homozygotes suggesting a dominant effect (odds ratio 1.302, CI = 1.129-1.503). Although further research is needed to prove that the Gln460Arg change has an aetiological role, it is so far the most convincing mutation to have been found with a role for increasing susceptibility to bipolar and genetically related unipolar disorders.

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Section: Discussionmentioning

confidence: 99%

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

et al. 2008

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“…Denlinger and colleagues (16) identified a putative lipopolysaccharide binding domain and went on to corroborate this sequence analysis with biochemical evidence that this putative domain actually binds lipopolysaccharide. In a large scale proteomic analysis, Kim and co-workers (17) identified numerous putative protein partners, many of which are thought to interact with the C-terminal region.…”

mentioning

confidence: 86%

P2X7 Receptor Cell Surface Expression and Cytolytic Pore Formation Are Regulated by a Distal C-terminal Region

Smart

Panchal

et al. 2003

Journal of Biological Chemistry

154

171

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The importance of the cytosolic C-terminal region of the P2X7 receptor (P2X7R) is unquestioned, yet little is known about the functional domains of this region and how they may contribute to the numerous properties ascribed to this receptor. A structure-function analysis of truncated and single-residue-mutated P2X7 receptors was performed in HEK-293 cells and Xenopus oocytes. Cells expressing receptors truncated at residue 581 (of 595) have negligible ethidium ion uptake, whereas those expressing the P2X7R truncated at position 582 give wild type ethidium ion uptake suggesting that pore formation requires over 95% of the C-terminal tail. Channel function was evident even in receptors that were truncated at position 380 indicating that only a small portion of the cytosolic region is required for channel activity. Surprisingly, truncations in the region between residues 551 and 581 resulted in non-functional receptors with no detectable cell surface expression in HEK-293 cells. A more detailed analysis revealed that mutations of single residues within this region could also abolish receptor function and cell surface expression, suggesting that this region may participate in regulating the surface expression of the pore-forming P2X7R.

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“…The N-and C-termini have residues related to selectivity and activity of the ion channel and interact with different membrane proteins including α-actin, receptor-like tyrosine phosphatase, and heat shock proteins [20]. The Cterminal tail is much longer for the P2X 7 R than for all the other P2XR family members and is involved in the majority of P2X 7 R functions [21]. It is essential for pore formation, receptor stabilization, and signal transduction.…”

Section: P2x 7 Rmentioning

confidence: 99%

The role of P2X7 receptors in tissue fibrosis: a brief review

Gentile

Natale

Lazzerini

et al. 2015

Purinergic Signalling

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Many previous studies have demonstrated that P2X 7 receptors (P2X 7 Rs) have a pleiotropic function in different pathological conditions and could represent a novel target for the treatment of a range of diseases. In particular, recent studies have explored the role of P2X 7 R in fibrosis, the pathological outcome of most chronic inflammatory diseases. The aim of this review is to discuss the biological features of P2X 7 R and summarize the current knowledge about the putative role of the P2X 7 R in triggering fibrosis in a wide spectrum of organs such as the lung, kidney, liver, pancreas, and heart.

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Cutting Edge: The Nucleotide Receptor P2X7 Contains Multiple Protein- and Lipid-Interaction Motifs Including a Potential Binding Site for Bacterial Lipopolysaccharide

Cited by 172 publications

References 41 publications

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

P2X7 Receptor Cell Surface Expression and Cytolytic Pore Formation Are Regulated by a Distal C-terminal Region

The role of P2X7 receptors in tissue fibrosis: a brief review

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