Allosteric modulation of ATP-gated P2X receptor channels

Coddou, Claudio; Stojilković, Stanko S.; Huidobro‐Toro, J. Pablo

doi:10.1515/rns.2011.014

Cited by 68 publications

(72 citation statements)

References 191 publications

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“…Extracellular protons represent an important regulatory factor for voltage and ligand-gated ion channels, and the P2X7R is subject to proton modulation [24]. Indeed, a previous study showed that extracellular protons potently inhibited P2X7R-dependent ion currents and the induction of membrane pore formation through the allosteric modulation of P2X7R channels [25].…”

Section: Acidic Extracellular Ph Inhibits P2x7r Ion Channel Functionsmentioning

confidence: 99%

Inflammasome activation by danger signals: extracellular ATP and pH

Takenouchi¹,

Tsukimoto²,

Hashimoto³

et al. 2014

Inflammasome

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Extracellular ATP has been recognized as a danger signal that alerts the innate immune system. High extracellular concentrations of ATP can trigger the maturation and secretion of pro-inflammatory cytokines (e.g., interleukin-1β and interleukin-18) through the inflammasome-dependent activation of caspase-1. The P2X7 receptor, an ATP-gated cation channel, plays a pivotal role in ATP-induced NLRP3 inflammasome assembly. Recently, intriguing evidence has emerged that acidic extracellular pH acts as a danger signal that activates inflammasomes. Extracellular acidification frequently occurs at sites of inflammation, infection, or injury. In addition, large amounts of ATP are readily released into the extracellular space from damaged cells at such sites. Thus, it is assumed that the ATP/P2X7 receptor pathway regulates the inflammatory response under acidic extracellular conditions. Here, we briefly discuss the mutual effects of extracellular ATP and pH on inflammasome activation and consider their roles in the regulation of inflammation.

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Section: Acidic Extracellular Ph Inhibits P2x7r Ion Channel Functionsmentioning

confidence: 99%

Inflammasome activation by danger signals: extracellular ATP and pH

Takenouchi¹,

Tsukimoto²,

Hashimoto³

et al. 2014

Inflammasome

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“…The isoforms share 26-54% sequence identity and each subunit is between 379 and 595 amino acids in length [136][137][138]. P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 isoforms form functional homomeric receptors, however heteromeric assemblies such as P2X2/3 and P2X1/5 channels are also possible [139,140]. P2X7 receptors are unique among the P2X receptor family because they fail to form heteromeric forms and are activated by high ATP concentrations (>100 M) [141].…”

Section: P2x Receptorsmentioning

confidence: 99%

“…Moreover, they show sodium and potassium permeability [136] and some of them are also permeable to chloride [147]. Aside from ATP, most P2X receptors are also activated by diadenosine polyphosphates or related dinucleotides and some nucleoside triphosphates [140,148].…”

Section: P2x Receptorsmentioning

confidence: 99%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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“…Furthermore, several endogenous and exogenous compounds can modulate ATP gating of these receptors, including essential trace metals, ivermectin, reactive oxygen species, phospholipids, and alcohols. The effects of these modulators are wide, including shifts in the EC 50 values, peak amplitude of current responses, and changes in pharmacological profiles (6).…”

mentioning

confidence: 99%

“…For example, Zn 2ϩ , a trace metal, inhibits the currents mediated by P2X1R, P2X3R, P2X5R, and P2X7R, whereas it potentiates the currents mediated by P2X2R and P2X4R (7). Copper, another trace element, potentiates the P2X2R but inhibits the activity of all other P2XRs (6,7). Specific residues that mediate cation effects, most probably participating in metal coordination, have been identified, and several cation-binding sites have been proposed (7).…”

mentioning

confidence: 99%

Role of domain calcium in purinergic P2X2 receptor channel desensitization

Coddou

Yan

Stojilković

2015

American Journal of Physiology-Cell Physiology

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Coddou C, Yan Z, Stojilkovic SS. Role of domain calcium in purinergic P2X2 receptor channel desensitization. Am J Physiol Cell Physiol 308: C729 -C736, 2015. First published February 11, 2015 doi:10.1152/ajpcell.00399.2014.-Activation of P2X2 receptor channels (P2X2Rs) is characterized by a rapid current growth accompanied by a decay of current during sustained ATP application, a phenomenon known as receptor desensitization. Using rat, mouse, and human receptors, we show here that two processes contribute to receptor desensitization: bath calcium-independent desensitization and calcium-dependent desensitization. Calcium-independent desensitization is minor and comparable during repetitive agonist application in cells expressing the full size of the receptor but is pronounced in cells expressing shorter versions of receptors, indicating a role of the COOH terminus in control of receptor desensitization. Calciumdependent desensitization is substantial during initial agonist application and progressively increases during repetitive agonist application in bath ATP and calcium concentration-dependent manners. Experiments with substitution of bath Na ϩ with N-methyl-D-glucamine (NMDG ϩ ), a large organic cation, indicate that receptor pore dilation is a calcium-independent process in contrast to receptor desensitization. A decrease in the driving force for calcium by changing the holding potential from Ϫ60 to ϩ120 mV further indicates that calcium influx through the channel pores at least partially accounts for receptor desensitization. Experiments with various receptor chimeras also indicate that the transmembrane and/or intracellular domains of P2X2R are required for development of calcium-dependent desensitization and that a decrease in the amplitude of current slows receptor desensitization. Simultaneous calcium and current recording shows development of calcium-dependent desensitization without an increase in global intracellular calcium concentrations. Combined with experiments with clamping intrapipette concentrations of calcium at various levels, these experiments indicate that domain calcium is sufficient to establish calcium-dependent receptor desensitization in experiments with whole-cell recordings.ATP; calcium; desensitization; pore dilation; purinergic receptors PURINERGIC P2X RECEPTORS (P2XRs) are ATP-gated nonselective cation channels expressed in various tissues and have multiple physiological roles (4, 30). Some notable examples of their roles in the central and peripheral nervous system include presynaptic P2X2Rs that contribute to an increase of glutamate release in mice interneurons (24), postsynaptic P2X4Rs that contribute to long-term potentiation in CA1 neurons from mice (34), involvement of P2X4Rs and P2X7Rs in neuropathic pain (10,36,37), and P2X3Rs and P2X2R acting through a heteromeric receptor for pain transmission in mammalian sensory neurons (28). On the other hand, the specific properties of each P2XR, such as ATP affinity (7), pore dilation (32), and kinetics of receptor desensitizati...

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Allosteric modulation of ATP-gated P2X receptor channels

Cited by 68 publications

References 191 publications

Inflammasome activation by danger signals: extracellular ATP and pH

Inflammasome activation by danger signals: extracellular ATP and pH

Ion Channels as Drug Targets in Central Nervous System Disorders

Role of domain calcium in purinergic P2X2 receptor channel desensitization

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