The human P2X7 receptor and its role in innate immunity
The human P2X7 receptor is a two-transmembrane ionotropic receptor which has aubiquitous distribution and is most highly expressed on immune cells. In macrophagesand similar myeloid cells primed by lipopolysaccharide (LPS), activation of P2X7 byextracellular ATP opens a cation channel/pore allowing massive K+ efflux associatedwith processing and secretion of pro-inflammatory cytokines interleukin (IL)-1ßand IL-18. A variety of other downstream effects follows P2X7 activation overseveral minutes including shedding of certain surface molecules, membrane blebbing,microvesicle/exosome release and apoptosis of the cell. High concentrations of ATP(>100 ¿M) are required to activate P2X7 but it remains unclear where these levelsexist, other than in inflammatory foci or confined spaces such as in bone. A varietyof potent selective antagonists of P2X7 activation have recently become available,allowing clinical trials to be undertaken in inflammatory and immune-mediateddisorders.Proteomic studies have shown that P2X7 exists as a large multiprotein complexwhich includes non-muscle myosin heavy chain and other elements of the cytoskeleton.In the absence of its ATP ligand and serum, P2X7 has an alternate function in therecognition and phagocytosis of non-opsonized foreign particles, including bacteriaand apoptotic cells. The P2RX7 gene has many polymorphic variants and isoformswhich increase or decrease function of the receptor. Genetic association studies havelinked loss-of-function polymorphisms with reactivation of latent tuberculosis as wellas symptomatic infection with certain other obligate intracellular pathogens. The manyroles involving P2X7 suggest that this receptor is essential to fundamental aspects ofthe innate immune response.
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