Molecular Physiology of P2X Receptors

Abstract

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 P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 channels and heteromeric P2X2/3 and P2X1/5 channels have been most fully characterized following heterologous expression. Some agonists (e.g., αβ-methylene ATP) and antagonists [e.g., 2′,3′- O-(2,4,6-trinitrophenyl)-ATP] are strongly selective for receptors containing P2X1 and P2X3subunits. All P2X receptors are permeable to small monovalent cations; some have significant calcium or anion permeability. In many cells, activation of homomeric P2X7 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, P2X7 receptor activation stimulates cytokine release by engaging intracellular signaling pathways.

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

“…The use of the BzATP agonist gave us an EC 50 of 263±22 mM (Figure 2c). This is in line with the fact that P2X 7 R are more sensitive to BzATP than to ATP (North, 2002). ATP-evoked currents from MDA-MB-435s cancer cells were inhibited by human P2X 7 R antagonists KN62 and A740003 ( Figure 2d and supplementary Figure 1a).…”

“…Extracellular ATP acts as a signalling molecule by activating plasma membrane G protein-coupled P2Y receptors and/or ligand-gated ion channels P2X receptors (Burnstock, 2006). Among the members of the P2X receptors family, the latest cloned P2X 7 receptors (P2X 7 R) (Rassendren et al, 1997) are very unique by different features, some of them are: (1) their sensitivity to ATP (North, 2002), (2) their facilitation under successive or sustained applications of agonist (Hibell et al, 2000;Roger et al, 2008Roger et al, , 2010a and (3) the appearance of a large, non-selective membrane pore after sustained stimulations with ATP (Pelegrin and Surprenant, 2006). Recently, several tumours have been shown to express P2X 7 R at unusually high levels (Adinolfi et al, 2002;Zhang et al, 2004;Slater et al, 2004a, b;Wang et al, 2004a;Raffaghello et al, 2006;Deli et al, 2007;Solini et al, 2008), however, their functionality and involvement in the physiology of cancer cells remain unclear.…”

Purinergic signalling-evoked intracellular Ca2+ concentration changes in the regulation of chondrogenesis and skeletal muscle formation

“…In migratory CPCs, we have recently confirmed the mRNA and protein level expression of certain P2X (P2X 1,4,5,6,7 , but not P2X 2 and P2X 3 ) and all P2Y receptors [86]. Our results suggest the functionality of P2Y 1 , P2Y 2 , P2Y 4 , as well as P2X 4 and P2X 6 receptor subtypes in CPCs, which shows a very good correlation with previous data implicating the P2 receptor subtypes P2X 6 , P2Y 4 and P2Y 14 to be key regulators in MSC commitment [91].…”

“…Today seven members of the ionotropic (P2X [1][2][3][4][5][6][7] ) and eight members of the metabotropic (P2Y 1,2,4,6,[11][12][13][14] ) purinergic receptors have been cloned and identified in mammals [13,14]. In 6 case of P2X receptors the seven members of the subfamily refer to seven distinct subunits as discussed below.…”

Hypoxia induced amoeboid microglial cell activation in postnatal rat brain is mediated by ATP receptor P2X4

“…As a group of membrane cation-selective receptor channels, P2X receptors interact with extracellular ATP [13]. It has been reported that ATP elicits discrete currents of P2X4R on microglia/macrophages [14]. In the latter, P2X4 receptors are involved in microglial activity in some pathological conditions.…”