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An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor

Ben J Gu1, Ronald Sluyter, Kristen K Skarratt

  • 1Department of Medicine, University of Sydney at Nepean Hospital, Penrith, New South Wales 2750, Australia.

The Journal of Biological Chemistry
|May 5, 2004
PubMed

Insights

A new P2X7 receptor polymorphism, R307Q, causes loss-of-function by preventing ATP binding. This discovery identifies a third common genetic variant impacting immune cell responses mediated by the P2X7 receptor.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • The P2X7 receptor (P2X7R) is a critical immune cell receptor involved in ATP-induced apoptosis.
  • Known loss-of-function polymorphisms (E496A, I568N) partially explain variations in P2X7R function.
  • Understanding P2X7R genetic variations is crucial for immune system research.

Purpose of the Study:

  • To identify and characterize novel loss-of-function polymorphisms in the human P2X7 receptor.
  • To investigate the functional consequences of a newly identified R307Q polymorphism on P2X7R activity.
  • To determine the impact of this polymorphism on ATP binding and receptor function.

Main Methods:

  • Genotyping of 420 subjects to identify P2X7R polymorphisms.
  • Functional assays measuring ion fluxes (Rb+, Ba2+, ethidium+) in monocytes and lymphocytes.
  • Transfection studies to assess P2X7R protein synthesis, surface expression, and function.
  • Monoclonal antibody binding assays to evaluate receptor-ligand interactions.

Main Results:

  • A novel heterozygous polymorphism, R307Q, was identified in 12 of 420 subjects.
  • The R307Q mutation resulted in absent or markedly decreased P2X7R channel and pore function.
  • R307Q P2X7R exhibited normal protein synthesis and surface expression but failed to bind a specific blocking antibody.
  • Monocyte-to-macrophage differentiation partially restored function in heterozygous R307Q cells, but double heterozygotes (R307Q/I568N) showed complete loss-of-function.

Conclusions:

  • The R307Q polymorphism represents a third significant loss-of-function variant of the human P2X7 receptor.
  • This polymorphism likely abolishes ATP binding to the extracellular domain of P2X7R, impacting immune cell signaling.
  • The findings contribute to understanding genetic variability in immune responses mediated by P2X7R.

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