ArticlePhysiological research2010
Roles of conserved ectodomain cysteines of the rat P2X4 purinoreceptor in agonist binding and channel gating.
Article in Physiological research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
- The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target.International journal of molecular sciences · 2022Review
- New Insights of the Zn(II)-Induced P2 × 4R Positive Allosteric Modulation: Role of Head Receptor Domain SS2/SS3, E160 and D170.International journal of molecular sciences · 2020Article
- To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors?Frontiers in pharmacology · 2020Review
- Insights into the channel gating of P2X receptors from structures, dynamics and small molecules.Acta pharmacologica Sinica · 2016Review
- Key sites for P2X receptor function and multimerization: overview of mutagenesis studies on a structural basis.Current medicinal chemistry · 2015Review
- Conformational flexibility of the agonist binding jaw of the human P2X3 receptor is a prerequisite for channel opening.British journal of pharmacology · 2014Article
- Heteromeric assembly of P2X subunits.Frontiers in cellular neuroscience · 2013Review
- Primitive ATP-activated P2X receptors: discovery, function and pharmacology.Frontiers in cellular neuroscience · 2013Review
- Conserved extracellular cysteines differentially regulate the potentiation produced by Zn2+ in rat P2X4 receptors.European journal of pharmacology · 2013Article
- Conserved ectodomain cysteines are essential for rat P2X7 receptor trafficking.Purinergic signalling · 2012Article
- Activation and regulation of purinergic P2X receptor channels.Pharmacological reviews · 2011Review
- Structural insights into the function of P2X4: an ATP-gated cation channel of neuroendocrine cells.Cellular and molecular neurobiology · 2010Review
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Mammalian P2X receptors contain 10 conserved cysteine residues in their ectodomains, which form five disulfide bonds (SS1-5). Here, we analyzed the relevance of these disulfide pairs in rat P2X4 receptor function by replacing one or both cysteines with alanine or threonine, expressing receptors in HEK293 cells and studying their responsiveness to ATP in the absence and presence of ivermectin, an allostenic modulator of these channels. Response to ATP was not altered when both cysteines forming the SS3 bond (C132-C159) were replaced with threonines. Replacement of SS1 (C116-C165), SS2 (C126-C149) and SS4 (C217-C227), but not SS5 (C261-C270), cysteine pairs with threonines resulted in decreased sensitivity to ATP and faster deactivation times. The maximum current amplitude was reduced in SS2, SS4 and SS5 double mutants and could be partially rescued by ivermectin in SS2 and SS5 double mutants. This response pattern was also observed in numerous single residue mutants, but receptor function was not affected when the 217 cysteine was replaced with threonine or arginine or when the 261 cysteine was replaced with alanine. These results suggest that the SS1, SS2 and SS4 bonds contribute substantially to the structure of the ligand binding pocket, while the SS5 bond located towards the transmembrane domain contributes to receptor gating.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.