P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40-50% identical in amino acid sequence. Each subunit has two transmembrane domains, separated by an extracellular domain (~280 amino acids). Channels form as multimers of several subunits. Homomeric P2X(1), P2X(2), P2X(3), P2X(4), P2X(5), and P2X(7) channels and heteromeric P2X(2/3) and P2X(1/5) channels have been most fully characterized following heterologous expression. Some agonists (e.g., alphabeta-methylene ATP) and antagonists [e.g., 2',3'-O-(2,4,6-trinitrophenyl)-ATP] are strongly selective for receptors containing P2X(1) and P2X(3) subunits. All P2X receptors are permeable to small monovalent cations; some have significant calcium or anion permeability. In many cells, activation of homomeric P2X(7) receptors induces a permeability increase to larger organic cations including some fluorescent dyes and also signals to the cytoskeleton; these changes probably involve additional interacting proteins. P2X receptors are abundantly distributed, and functional responses are seen in neurons, glia, epithelia, endothelia, bone, muscle, and hemopoietic tissues. The molecular composition of native receptors is becoming understood, and some cells express more than one type of P2X receptor. On smooth muscles, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., in ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several viscera (e.g., bladder, intestine) and play a key role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles for ATP signaling through P2X receptors are likely in neurohypophysis, ducted glands, airway epithelia, kidney, bone, and hemopoietic tissues. In the last case, P2X(7) receptor activation stimulates cytokine release by engaging intracellular signaling pathways.
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