Genetic polymorphisms of the human P2X7 receptor and relationship to function

Extracellular ATP has been shown to induce apoptotic death of many cell types of hematopoietic origin. This action of ATP is mediated via activation of P2X7 purinergic receptors, which show the unusual property of time‐dependent channel dilation to accept permeants as large as ethidium cation (314 Da). P2X7 function, measured by area under the ATP‐induced ethidium uptake curve, was 5‐fold greater for monocytes than lymphocytes, while polymorphs and platelets showed no ethidium uptake. Expression of P2X7 receptor, measured by the binding of a monoclonal antibody, was also 5‐fold greater on monocytes than lymphocytes. However, in some subjects, both normal and with chronic lymphocytic leukemia, the P2X7 receptor was nonfunctional despite good expression of P2X7 protein. Three single nucleotide polymorphisms were found in the P2X7 cDNA coding region, one of which correlated with P2X7 function. Thus, the homozygous substitution of alanine for glutamic acid at amino acid 496 led to complete loss of function of the P2X7 receptor, while the heterozygous polymorphism gave function half that of the germline P2X7 receptor. Drug Dev. Res. 53:72–76, 2001.