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 P2X(7) purinergic receptors, which show the unusual property of time-dependent channel dilation to accept permeants as large as ethidium cation (314 Da). P2X(7) 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 P2X(7) 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 P2X(7) receptor was nonfunctional despite good expression of P2X7 protein. Three single nucleotide polymorphisms were found in the P2X(7) cDNA coding region, one of which correlated with P2X(7) function. Thus, the homozygous substitution of alanine for glutamic acid at amino acid 496 led to complete loss of function of the P2X(7) receptor, while the heterozygous polymorphism gave function half that of the germline P2X(7) receptor. (C) 2001 Wiley-Liss, Inc.