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Published on: May 18, 2009

An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor

James S Wiley1, Lan-Phuong Dao-Ung, Changping Li

  • 1Department of Medicine, University of Sydney at Nepean Hospital, Penrith, New South Wales 2750, Australia. wileyj@medicine.usyd.edu.au

The Journal of Biological Chemistry
|February 15, 2003
PubMed

Insights

A second P2X(7) receptor polymorphism (Ile-568 to Asn) causes loss-of-function, reducing receptor activity to 25% of normal. This Ile-568 variant is critical for P2X(7) receptor cell surface expression and function.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • The P2X(7) receptor, highly expressed on mononuclear cells, mediates ATP-induced apoptosis.
  • Variations in P2X(7) receptor function are partly due to a known loss-of-function polymorphism (Glu-496 to Ala).

Purpose of the Study:

  • To identify and characterize a second loss-of-function polymorphism in the P2X(7) receptor.
  • To investigate the functional impact of the Ile-568 to Asn polymorphism on P2X(7) receptor activity and expression.

Main Methods:

  • Assessed P2X(7) receptor function via ATP-induced ion fluxes (Rb+, Ba2+, ethidium+) in lymphocyte subsets.
  • Measured P2X(7) receptor expression on lymphocytes using fluorescein-conjugated monoclonal antibody binding.
  • Utilized transfection experiments to evaluate the functional consequences of the Ile-568 to Asn mutation.
  • Examined the effect of interferon-gamma-induced monocyte differentiation on P2X(7) receptor function.

Main Results:

  • A novel polymorphism, Ile-568 to Asn, was identified in P2X(7) receptor in normal subjects and chronic lymphocytic leukemia patients.
  • Lymphocytes with the Ile-568 to Asn polymorphism exhibited reduced P2X(7) function (approx. 25% of normal) and decreased receptor expression (approx. 50% of normal).
  • Transfection studies confirmed that the Ile-568 to Asn mutation renders the P2X(7) receptor non-functional due to impaired cell surface expression.
  • Monocyte differentiation to macrophages partially restored P2X(7) function in heterozygous cells (approx. 50% of normal).

Conclusions:

  • The Ile-568 to Asn substitution represents a second significant loss-of-function polymorphism for the P2X(7) receptor.
  • The residue at position 568 is crucial for the P2X(7) receptor's trafficking domain, located between residues 551 and 581.
  • This polymorphism contributes to the observed variability in P2X(7) receptor function in human populations.

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