Neuronal P2X transmitter-gated cation channels change their ion selectivity in seconds

Khakh, Baljit S.; Bao, Xiaoyan; Labarca, Cesar; Lester, Henry A.

doi:10.1038/7233

Cited by 335 publications

(386 citation statements)

References 47 publications

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“…This suggested that the permeability of the channel coupled to P2X 4 receptors could increase, allowing the passage of molecules of up to 375 Da, which corresponds to the value of the ionized form of YOPRO-1 in solution. This is in agreement with the results of Khakh et al [31] who reported that P2X 4 receptors expressed in oocytes could eventually form a pore after prolonged stimulation. The mechanism involved in this increased permeability remains to be determined.…”

Section: Discussionsupporting

confidence: 93%

“…This is in agreement with our results showing a lack of effect of carbenoxolone and 10 panx1 on the P2X 4 -receptor associated uptake of YOPRO-1, and with the results of Chaumont and Kahkh [34] who reported that pannexin-1 channels did not contribute to P2X 2 receptor permeability increase. Khakh et al suggested that the changes in permeability of P2X 2 and P2X 4 receptors could be controlled at least in part by the second transmembrane domain or by conformational changes in the cytosolic domain, remote from the selectivity filter itself [31,34].…”

Section: Discussionmentioning

confidence: 99%

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Ivermectin-dependent release of IL-1beta in response to ATP by peritoneal macrophages from P2X7-KO mice

Seil

Ouaaliti

Etxebarria

et al. 2010

Purinergic Signalling

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The response to ATP of peritoneal macrophages from wild-type (WT) and P2X 7 -invalidated (KO) mice was tested. Low concentrations (1-100 μM) of ATP transiently increased the intracellular concentration of calcium ([Ca 2+ ] i ) in cells from both mice. The inhibition of the polyphosphoinositide-specific phospholipase C with U73122 inhibited this response especially in WT mice suggesting that the responses coupled to P2Y receptors were potentiated by the expression of P2X 7 receptors. One millimolar ATP provoked a sustained increase in the [Ca 2+ ] i only in WT mice. The response to 10 μM ATP was potentiated and prolonged by ivermectin in both mice. One millimolar ATP increased the influx of extracellular calcium, decreased the intracellular concentration of potassium ([K + ] i ) and stimulated the secretion of interleukin-1β (IL-1β) only in cells from WT mice. Ten micromolar ATP in combination with 3 μM ivermectin reproduced these responses both in WT and KO mice. The secretion of IL-1β was also increased by nigericin in WT mice and the secretory effect of a combination of ivermectin with ATP in KO mice was suppressed in a medium containing a high concentration of potassium. In WT mice, 150 μM BzATP stimulated the uptake of YOPRO-1. Incubation of macrophages from WT and KO mice with 10 μM ATP resulted in a small increase of YOPRO-1 uptake, which was potentiated by addition of 3 μM ivermectin. The uptake of this dye was unaffected by pannexin-1 blockers. In conclusion, prolonged stimulation of P2X 4 receptors by a combination of low concentrations of ATP plus ivermectin produced a sustained activation of the non-selective cation channel coupled to this receptor. The ensuing variations of the [K + ] i triggered the secretion of IL-1β. Pore formation was also triggered by activation of P2X 4 receptors. Higher concentrations of ATP elicited similar responses after binding to P2X 7 receptors. The expression of the P2X 7 receptors was also coupled to a better response to P2Y receptors.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Ivermectin-dependent release of IL-1beta in response to ATP by peritoneal macrophages from P2X7-KO mice

Seil

Ouaaliti

Etxebarria

et al. 2010

Purinergic Signalling

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“…Conversely, if P2X 4/7 heteromeric receptors were present, we should have observed an increase on the peak currents after 3 min of incubation with 3 μM ivermectin, a fact not seen in our results [4,19]. Heteromeric P2X 4/6 receptors show high affinity for αβMeATP (threshold=10 μM) [25]. Nevertheless, purinergic receptors in mouse Leydig cells do not present purinergic currents after stimulation with 100 μM αβMeATP [41].…”

Section: Discussionmentioning

confidence: 62%

“…The action at the lower affinity binding site (EC 50 =2 µM) results in a slower deactivation rate and enhancement of the ATP affinity [43]. Moreover, ivermectin does not act on P2X 2 , P2X 3 , P2X 2/3 , and P2X 7 receptors but does so on heteromeric channels containing the P2X 4 subunit [25,4,19]. After ATP stimulation of Leydig cells, we observed a 30% non-reversible increased in the peak currents subsequent to the incubation with 0.5 μM ivermectin (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mouse Leydig cells express multiple P2X receptor subunits

Antonio

Costa

Gomes

et al. 2008

Purinergic Signalling

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ATP acts on cellular membranes by interacting with P2X (ionotropic) and P2Y (metabotropic) receptors. Seven homomeric P2X receptors (P2X 1 -P2X 7 ) and seven heteromeric receptors (P2X 1/2 , P2X 1/4 , P2X 1/5 , P2X 2/3 , P2X 2/6 , P2X 4/6 , P2X 4/7 ) have been described. ATP treatment of Leydig cells leads to an increase in [Ca 2+ ] i and testosterone secretion, supporting the hypothesis that Ca 2+ signaling through purinergic receptors contributes to the process of testosterone secretion in these cells. Mouse Leydig cells have P2X receptors with a pharmacological and biophysical profile resembling P2X 2 . In this work, we describe the presence of several P2X receptor subunits in mouse Leydig cells. Western blot experiments showed the presence of P2X 2 , P2X 4 , P2X 6 , and P2X 7 subunits. These results were confirmed by immunofluorescence. Functional results support the hypothesis that heteromeric receptors are present in these cells since 0.5 μM ivermectin induced an increase (131.2±5.9%) and 3 μM ivermectin a decrease (64.2±4.8%) in the whole-cell currents evoked by ATP. These results indicate the presence of functional P2X 4 subunits. P2X 7 receptors were also present, but they were non-functional under the present conditions because dye uptake experiments with Lucifer yellow and ethidium bromide were negative. We conclude that a heteromeric channel, possibly P2X 2/4/6 , is present in Leydig cells, but with an electrophysiological and pharmacological phenotype characteristic of the P2X 2 subunit.

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“…P2X receptors include two transmembrane spanning regions, an extracellular loop and intracellular N-and C-termini. The extracellular loop contains the ATP binding site and the sites for antagonists and modulators; the residues in the C-terminal play an important role in determining the rate of desensitization [6] . P2X receptors are cation-selective channels with low affinity for ATP.…”

Section: P2 Receptor Subtypesmentioning

confidence: 99%

Therapeutic potential of extracellular ATP and P2 receptors in nervous system diseases

Tu¹,

Wang²

2009

Neurosci. Bull.

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Extracellular adenosine 5'-triphosphate (ATP) is a key signaling molecule present in the central nervous system (CNS), and now is receiving greater attention due to its role as a messenger in the CNS during different physiological and pathological events. ATP is released into the extracellular space through vesicular exocytosis or from damaged and dying cells. Once in the extracellular environment, ATP binds to the specific receptors termed P2, which mediate ATP effects and are present broadly in both neurons and glial cells. There are P2X, the ligand-gated ionotropic receptors, possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, the metabotropic G-protein-coupled receptors, possessing high affinity for ATP. Since massive extracellular release of ATP often occurs after stress, brain ischemia and trauma, the extracellular ATP is considered relating to or involving in the pathological processes of many nervous system diseases. Conversely, the trophic functions have also been extensively described for the extracellular ATP. Therefore, extracellular ATP plays a very complex role in the CNS and its binding to P2 receptors can be related to toxic and/or beneficial effects. In this review, we described the extracellular ATP acting via P2 receptors as a potent therapeutic target for treatment of nervous system diseases.

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Neuronal P2X transmitter-gated cation channels change their ion selectivity in seconds

Cited by 335 publications

References 47 publications

Ivermectin-dependent release of IL-1beta in response to ATP by peritoneal macrophages from P2X7-KO mice

Ivermectin-dependent release of IL-1beta in response to ATP by peritoneal macrophages from P2X7-KO mice

Mouse Leydig cells express multiple P2X receptor subunits

Therapeutic potential of extracellular ATP and P2 receptors in nervous system diseases

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