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Proteomics to Identify Proteins Interacting with P2X2 Ligand-Gated Cation Channels
Published on: May 19, 2009
Cutting edge: a natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor
Sahil Adriouch1, Claudia Dox, Vivienne Welge
1Université Denis Diderot, Paris, France.
Abstract:
The P2X7 receptor (P2X(7)R) is an ATP-gated channel that mediates apoptosis of cells of the immune system. The capacity of P2X(7)R to form large pores depends on its large cytoplasmic tail, which harbors a putative TNFR-related death domain. Previous transfection studies indicated that mouse P2X(7)R forms pores much less efficiently than its counterparts from humans and rats. In this study, we demonstrate that an allelic mutation (P451L) in the predicted death domain of P2X(7)R confers a drastically reduced sensitivity to ATP-induced pore formation in cells from some commonly used strains of mice, i.e., C57BL/6 and DBA/2. In contrast, most other strains of mice, including strains derived from wild mice, carry P451 at this position as do rats and humans. The effects of the P451L mutation resemble those of the E496A mutation in human P2X(7)R. These P2X(7)R mutants may provide useful tools to decipher the molecular mechanisms leading to pore formation.
Insights
A specific mutation (P451L) in the P2X7 receptor (P2X(7)R) significantly reduces its ability to form pores in immune cells of certain mouse strains. This finding aids in understanding P2X(7)R pore formation mechanisms.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The P2X7 receptor (P2X(7)R) is an ATP-gated ion channel crucial for immune cell apoptosis.
- Its pore-forming capacity relies on a cytoplasmic tail with a death domain.
- Mouse P2X(7)R exhibits lower pore formation efficiency compared to human and rat counterparts.
Purpose of the Study:
- To investigate the role of an allelic mutation (P451L) in the P2X(7)R death domain on ATP-induced pore formation.
- To compare the pore formation efficiency of different mouse strains carrying specific P2X(7)R variants.
Main Methods:
- Utilized transfection studies to analyze P2X(7)R function.
- Examined ATP-induced pore formation in immune cells from various mouse strains.
- Compared the P451L mutation's effects with known mutations like E496A in human P2X(7)R.
Main Results:
- Identified a P451L mutation in the P2X(7)R death domain.
- Demonstrated that this mutation drastically reduces ATP-induced pore formation in C57BL/6 and DBA/2 mouse strains.
- Observed that most other mouse strains, rats, and humans possess the P451 variant.
Conclusions:
- The P451L mutation in P2X(7)R significantly impairs pore formation in specific mouse models.
- This allelic variation explains differences in P2X(7)R function across mouse strains.
- P2X(7)R mutants, like P451L, are valuable tools for elucidating pore formation mechanisms.
