Signal Transduction by P2-Purinergic Receptors for Extracellular ATP

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Abstract
Extracellular adenosine triphosphate (ATP), at micromolar/nanomolar concentrations, has been shown to induce significant functional changes in a wide variety of normal and transformed cell types. While ATP can be nonspecifically released from the cytosol of damaged cells, it is also co-packaged in certain exocytotic vesicles/granules containing conventional neurotransmitters and hormones. The diverse biologic responses to ATP appear to be mediated by a variety of so-called P2-purinergic, cell surface receptors that are activated upon binding ATP and other nucleotides. Recent physiologic, biochemical, and pharmacologic studies suggest that there are multiple ATP receptor subtypes. These include: (1) G-protein-coupled ATP receptors, which stimulate inositol phospholipid hydrolysis, Ca2+ mobilization, and activation of protein kinase C; (2) ATP receptors that directly activate nonselective cation channels in the plasma membranes of a variety of excitable cell types; and (3) ATP receptors that, via the rapid induction of surface membranes pores permeable to both ions and endogenous metabolites, can produce cytotoxic or activation responses in T lymphocytes and other immune effector cells. In addition to these functional criteria, these putative ATP receptor subtypes can be distinguished by characteristic selectivities for a variety of structurally modified ATP analogs. Current research is directed towards the identification, isolation, and structural characterization of these receptors by both biochemical and molecular biologic approaches.