Genetic polymorphisms of the human P2X(7) receptor and relationship to function

Extracellular ATP has been shown to induce apoptotic death of many cell typ es of hematopoietic origin. This action of ATP is mediated via activation o f P2X(7) purinergic receptors, which show the unusual property of time-depe ndent channel dilation to accept permeants as large as ethidium cation (314 Da). P2X(7) function, measured by area under the ATP-induced ethidium upta ke curve, was 5-fold greater for monocytes than lymphocytes, while polymorp hs and platelets showed no ethidium uptake. Expression of P2X(7) receptor, measured by the binding of a monoclonal antibody, was also 5-fold greater o n monocytes than lymphocytes. However, in some subjects, both normal and wi th chronic lymphocytic leukemia, the P2X(7) receptor was nonfunctional desp ite good expression of P2X7 protein. Three single nucleotide polymorphisms were found in the P2X(7) cDNA coding region, one of which correlated with P 2X(7) function. Thus, the homozygous substitution of alanine for glutamic a cid at amino acid 496 led to complete loss of function of the P2X(7) recept or, while the heterozygous polymorphism gave function half that of the germ line P2X(7) receptor. (C) 2001 Wiley-Liss, Inc.