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Basal Release of ATP: An Autocrine-Paracrine Mechanism for Cell Regulation

Virtually every type of eukaryotic cell is regulated by adenosine triphosphate (ATP) and other nucleotides, such as uridine triphosphate (UTP), that the cells release themselves (autocrine signaling) or that are released by neighboring cells (paracrine signaling). Signaling in response to released nucleotides occurs through the activation of plasma membrane–localized P2 receptors: the P2X ion channels and the P2Y heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors. Release of ATP and alteration of cellular function also occur under “basal” conditions. Such basal release of ATP, which can be increased by minimal perturbation of cells through physical or chemical stimuli, influences a wide array of physiological events, including tissue blood flow, ion transport, growth and metastatic potential of malignant cells, endocrine and neuronal activity, neural development, musculoskeletal and renal function, stem cell proliferation, and response to pathogens. This Review, which contains two figures and 216 references, discusses the diverse array of receptors for ATP (and its major hydrolytic product adenosine) and the range of enzymes (including ecto–adenosine triphosphatases and kinases) that regulate extracellular concentrations of ATP, which create a highly versatile and tightly regulated system for the regulation of cell and tissue function by extracellular ATP that is derived from intracellular pools of nucleotides.

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