Molecular properties of ATP-gated P2X receptor ion channels

Vial, Céline; Roberts, Jonathan A.; Evans, Richard J.

doi:10.1016/j.tips.2004.07.008

Cited by 112 publications

(132 citation statements)

References 83 publications

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“…Rat coronary arteries express P2X 4 receptors [43,44] in addition to P2X 1 receptors. P2X 4 receptors are, however, less sensitive to stimulation by α,β-methylene-ATP [26,27,44] and are not blocked by NF449 in concentrations up to 30 μM [43]. This argues against an involvement of P2X 4 receptors in the observed responses of human coronary smooth muscle cells to α,β-methylene-ATP.…”

Section: Discussionmentioning

confidence: 99%

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P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

Hinze

Mayer

Harst

et al. 2013

Purinergic Signalling

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Adenine nucleotides acting at P2X 1 receptors are potent vasoconstrictors. Recently, we demonstrated that activation of adenosine A 2B receptors on human coronary smooth muscle cells inhibits cell proliferation by the induction of the nuclear receptor subfamily 4, group A, member 1 (NR4A1; alternative notation Nur77). In the present study, we searched for long-term effects mediated by P2X 1 receptors by analyzing receptor-mediated changes in cell proliferation and in the expression of NR4A1. Cultured human coronary smooth muscle cells were treated with selective receptor ligands. Effects on proliferation were determined by counting cells and measuring changes in impedance. The induction of transcription factors was assessed by qPCR. The P2X receptor agonist α,β-methylene-ATP and its analog β,γ-methylene-ATP inhibited cell proliferation by about 50 % after 5 days in culture with half-maximal concentrations of 0.3 and 0.08 μM, respectively. The effects were abolished or markedly attenuated by the P2X 1 receptor antagonist NF449 (carbonylbis-imino-benzenetriylbis-(carbonylimino)tetrakis-benzene-1,3-disulfonic acid; 100 nM and 1 μM). α,β-methylene-ATP and β,γ-methylene-ATP applied for 30 min to 4 h increased the expression of NR4A1; NF449 blocked or attenuated this effect. Small interfering RNA directed against NR4A1 diminished the antiproliferative effects of α,β-methylene-ATP and β,γ-methylene-ATP. α,β-methylene-ATP (0.1 to 30 μM) decreased migration of cultured human coronary smooth muscle cells in a chamber measuring changes in impedance; NF449 blocked the effect. In conclusion, our results demonstrate for the first time that adenine nucleotides acting at P2X 1 receptors inhibit the proliferation of human coronary smooth muscle cells via the induction of the early gene NR4A1.

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Section: Discussionmentioning

confidence: 99%

“…The P2X receptor agonist α,β-methylene-ATP [26][27][28] failed to affect the proliferation of cultured smooth muscle cells derived from rat aorta [11,29]. However, culturing of vascular smooth muscle cells has been reported to possibly cause a loss in the expression of P2X 1 receptors [30,31].…”

Section: Introductionmentioning

confidence: 99%

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

Hinze

Mayer

Harst

et al. 2013

Purinergic Signalling

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“…Burnstock's early hypothesis that ATP, the major intracellular molecule providing the energy required for multiple biochemical and biophysical processes, may actually function as an extracellular non-adrenergic and noncholinergic signaling molecule [12,13] was received with great skepticism [14,15]. After several decades of extensive work, the scientific community came to the realization that ATP is widely employed as a signaling molecule in multiple biological processes in both normal and pathophysiological conditions [9,11,[16][17][18][19][20][21][22][23][24]. The rapid progress in understanding and deciphering multiple molecular mechanisms of signaling revealed that ATP is a potent mediator of multiple signaling cascades, which may act through binding to, and nonhydrolytic activation of, P2X ionotropic receptors or G Electronic supplementary material The online version of this article (doi:10.1007/s11302-016-9520-9) contains supplementary material, which is available to authorized users.…”

Section: Introductionmentioning

confidence: 99%

“…protein-coupled P2Y receptors [1,3,19,21,[23][24][25][26][27][28]. Although multiple past studies focused on understanding the implications of ATP-controlled signaling with respect to endogenous transmembrane transporters such as ion channels [17,19,20,24,[28][29][30][31], there is a recent interest in understanding how ATP controls the lytic action of pore-forming toxins (PFTs) [22,26,27,[32][33][34].…”

Section: Introductionmentioning

confidence: 99%

“…Although multiple past studies focused on understanding the implications of ATP-controlled signaling with respect to endogenous transmembrane transporters such as ion channels [17,19,20,24,[28][29][30][31], there is a recent interest in understanding how ATP controls the lytic action of pore-forming toxins (PFTs) [22,26,27,[32][33][34]. PFTs introduce unregulated conducting pathways into the host cell plasmalemma [35][36][37][38][39], which is expected to yield direct cytolysis.…”

Section: Introductionmentioning

confidence: 99%

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Purinergic control of lysenin’s transport and voltage-gating properties

Bryant

Shrestha

Carnig

et al. 2016

Purinergic Signalling

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Lysenin, a pore-forming protein extracted from the coelomic fluid of the earthworm Eisenia foetida, manifests cytolytic activity by inserting large conductance pores in host membranes containing sphingomyelin. In the present study, we found that adenosine phosphates control the biological activity of lysenin channels inserted into planar lipid membranes with respect to their macroscopic conductance and voltage-induced gating. Addition of ATP, ADP, or AMP decreased the macroscopic conductance of lysenin channels in a concentration-dependent manner, with ATP being the most potent inhibitor and AMP the least. ATP removal from the bulk solutions by buffer exchange quickly reinstated the macroscopic conductance and demonstrated reversibility. Singlechannel experiments pointed to an inhibition mechanism that most probably relies on electrostatic binding and partial occlusion of the channel-conducting pathway, rather than ligand gating induced by the highly charged phosphates. The Hill analysis of the changes in macroscopic conduction as a function of the inhibitor concentration suggested cooperative binding as descriptive of the inhibition process. Ionic screening significantly reduced the ATP inhibitory efficacy, in support of the electrostatic binding hypothesis. In addition to conductance modulation, purinergic control over the biological activity of lysenin channels has also been observed to manifest as changes of the voltage-induced gating profile. Our analysis strongly suggests that not only the inhibitor's charge but also its ability to adopt a folded conformation may explain the differences in the observed influence of ATP, ADP, and AMP on lysenin's biological activity.

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Overview of Drug Discovery and Development

Ator¹,

Mallamo²,

Williams³

2006

CP Pharmacology

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This overview unit describes the core activities involved in the drug discovery and development process, from target identification - including preclinical biology, medicinal and process chemistry - to pharmacokinetics and metabolism (ADME), and also activities related to the to the drug approval process. The latter include the activities related to the filing of an IND (Investigational New Drug) application and also Phases I - III of clinical trials that form the basis of an NDA (New Drug Application) submission, as well as post-marketing Phase IV activities as required by the U.S. Food and Drug Administration (FDA) and the European and Japanese counterparts.

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Molecular properties of ATP-gated P2X receptor ion channels

Cited by 112 publications

References 83 publications

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

Purinergic control of lysenin’s transport and voltage-gating properties

Overview of Drug Discovery and Development

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