Cytolytic P2X purinoceptors

Virgilio, Francesco Di; Chiozzi, Paola; Falzoni, Simonetta; Ferrari, Davide; Sanz, Juana María; Venketaraman, Vishwanath; Baricordi, Olavio R.

doi:10.1038/sj.cdd.4400341

Cited by 258 publications

(272 citation statements)

References 97 publications

(105 reference statements)

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“…P2X 7 R is an intriguing receptor from which pharmacological activation is generally associated to cytotoxic effects (Surprenant et al, 1996;Di Virgilio et al, 1998) therefore leading to the hypothesis that their overexpression or stimulation could be deleterious for cells. Surprisingly, it was found that P2X 7 R is expressed at very high levels in several tumours, compared with Deli et al, 2007;Solini et al, 2008) and was even proposed to represent an early cancer marker (Slater et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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ATP-gated P2X 7 receptors (P2X 7 R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X 7 R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X 7 R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X 7 receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca 2 þ -activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X 7 R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X 7 R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X 7 R antagonists.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…3A-E). P2X 7 receptor activation induces membrane blebbing, membrane permeabilization to large cations such as propidium iodide (PI), and eventually leads to cell death (Di Virgilio et al, 1998;North, 2002). ATP-induced permeability to PI was observed in all individually identified cholinergic cells we tested (33/33 cells; Fig.…”

Section: E-atp Causes Death Of the Cholinergic Neurons In Normal Retimentioning

confidence: 99%

“…e-ATP can activate cell death in different non-neural cell populations (Di Virgilio et al, 1998). Investigations were therefore carried out to determine whether blocking e-ATP increased the number of cholinergic cells by preventing cell death among these neurons.…”

Section: E-atp Causes Death Of the Cholinergic Neurons In Normal Retimentioning

confidence: 99%

“…Upon sustained or repeated activation, the P2X 7 receptors induce large non-selective membrane pores, which eventually lead to cell death (Di Virgilio et al, 1998;North, 2002). P2X 7 receptors have been shown to be expressed in regions of the nervous system (North, 2002) and, therefore investigations were undertaken to determine whether endogenous e-ATP is involved in controlling the number and density of cells in specific neural populations.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal death induced by endogenous extracellular ATP in retinal cholinergic neuron density control

et al. 2005

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The precise assembly of neuronal circuits requires that the correct number of pre- and postsynaptic neurons form synaptic connections. Neuronal cell number is thus tightly controlled by cell death during development. Investigating the regulation of cell number in the retina we found an ATP gated mechanism of neuronal death control. By degrading endogenous extracellular ATP or blocking the P2X7 ATP receptors we found that endogenous extracellular ATP triggers the death of retinal cholinergic neurons during normal development. ATP-induced death eliminates cholinergic cells too close to one another, thereby controlling the total number, the local density and the regular spacing of these neurons.

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“…Functional P2X7Rs are homotrimers [28] abundantly expressed in cells of immunological origin or function, in particular macrophages [43], mast cells [7], and microglia [49], as well as in some types of cancer [31,42]. The receptor exhibits low sensitivity to ATP, does not desensitize, and gradually develops permeability to organic cations, causing a sustained current growth accompanied by cell blebbing and death [1,12,32,45,50]. The C-terminus of P2X7R is longest among P2XRs and was suggested to account for many of these receptor-specific characteristics [2,41,45].…”

Section: Introductionmentioning

confidence: 99%

Conserved ectodomain cysteines are essential for rat P2X7 receptor trafficking

Jindrichova

Kuzyk

Li³

et al. 2012

Purinergic Signalling

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The P2X7 receptor (P2X7R) is a member of the ATP-gated ion channel family that exhibits distinct electrophysiological and pharmacological properties. This includes low sensitivity to ATP, lack of desensitization, a sustained current growth during prolonged receptor stimulation accompanied with development of permeability to large organic cations, and the coupling of receptor activation to cell blebbing and death. The uniquely long C-terminus of P2X7R accounts for many of these receptor-specific functions. The aim of this study was to understand the role of conserved ectodomain cysteine residues in P2X7R function. Single-and double-point threonine mutants of C119-C168, C129-C152, C135-C162, C216-C226, and C260-C269 cysteine pairs were expressed in HEK293 cells and studied using whole-cell current recording. All mutants other than C119T-P2X7R responded to initial and subsequent application of 300-μM BzATP and ATP with small amplitude monophasic currents or were practically nonfunctional. The mutagenesis-induced loss of function was due to decreased cell-surface receptor expression, as revealed by assessing levels of biotinylated mutants. Coexpression of all double mutants with the wild-type receptor had a transient or, in the case of C119T/C168T double mutant, sustained inhibitory effect on receptor trafficking. The C119T-P2X7R mutant was expressed on the plasma membrane and was fully functional with a slight decrease in the sensitivity for BzATP, indicating that interaction of liberated Cys168 with another residue rescues the trafficking of receptor. Thus, in contrast to other P2XRs, all disulfide bonds of P2X7R are individually essential for the proper receptor trafficking.

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Cytolytic P2X purinoceptors

Cited by 258 publications

References 97 publications

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

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

Neuronal death induced by endogenous extracellular ATP in retinal cholinergic neuron density control

Conserved ectodomain cysteines are essential for rat P2X7 receptor trafficking

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