Neuromodulation by Extracellular ATP and P2X Receptors in the CNS

Khakh, Baljit S.; North, Richard

doi:10.1016/j.neuron.2012.09.024

Cited by 297 publications

(325 citation statements)

References 210 publications

(297 reference statements)

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“…When it comes to other special sites of the P2X receptor, ATP binding sites (motifs 12, 1, 8, and 5) and five disulfide bonds in extracellular domains are quite conserved among all the vertebrates and invertebrates. Although the sites directly participating in ATP binding are conserved among subtypes, the affinities for ATP are quite distinct among different subtypes [59]. Based on mutagenesis studies on P2X7 receptors, residues around the ATP binding sites are likely to contribute to the sensitivity to ATP [60,61].…”

Section: Mmu-p2x1mentioning

confidence: 99%

Comparative study of the P2X gene family in animals and plants

Hou

Cao

2016

Purinergic Signalling

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P2X receptors are ligand-gated ion channels that can bind with the adenosine triphosphate (ATP) and have diverse functional roles in neuropathic pain, inflammation, special sense, and so on. In this study, 180 putative P2X genes, including 176 members in 32 animal species and 4 members in 3 species of lower plants, were identified. These genes were divided into 13 groups, including 7 groups in vertebrates and 6 groups in invertebrates and lower plants, through phylogenetic analysis. Their gene organization and motif composition are conserved in most predicted P2X members, while groupspecific features were also found. Moreover, synteny relationships of the putative P2X genes in vertebrates are conserved while simultaneously experiencing a series of gene insertion, inversion, and transposition. Recombination signals were detected in almost all of the vertebrates and invertebrates, suggesting that intragenic recombination may play a significant role in the evolution of P2X genes. Selection analysis also identified some positively selected sites that acted on the evolution of most of the predicted P2X proteins. The phenomenon of alternative splicing occurred commonly in the putative P2X genes of vertebrates. This article explored in depth the evolutional relationship among different subtypes of P2X genes in animal and plants and might serve as a solid foundation for deciphering their functions in further studies.

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Section: Mmu-p2x1mentioning

confidence: 99%

Comparative study of the P2X gene family in animals and plants

Hou

Cao

2016

Purinergic Signalling

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“…The channel activity is poorly desensitising, and prolonged or repeated exposure to ATP typically results in a pore formation, allowing large organic cations to enter the cell and eventually triggering cell death [1,5]. Several mechanisms have been proposed for the channelto-pore transition, which may be caused by intrinsic properties of P2X7 or by P2X7-associated proteins ( [6] and references therein). P2X7 activation affects a wide range of cellular functions, such as changes in the intracellular concentrations of Ca 2+ or K + , release of gliotransmitters and cytokines, phagocytosis, cell proliferation or death.…”

Section: Introductionmentioning

confidence: 99%

Natural compounds with P2X7 receptor-modulating properties

Fischer

Urban

Immig

et al. 2013

Purinergic Signalling

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The adenosine 5′-triphosphate (ATP)-gated P2X7 receptor is a membrane-bound, non-selective cation channel, expressed in a variety of cell types. The P2X7 senses high extracellular ATP concentrations and seems to be implicated in a wide range of cellular functions as well as pathophysiological processes, including immune responses and inflammation, release of gliotransmitters and cytokines, cancer cell growth or development of neurodegenerative diseases. In the present study, we identified natural compounds and analogues that can block or sensitize the ATP (1 mM)-induced Ca 2+ response using a HEK293 cell line stably expressing human P2X7 and fluorometric imaging plate reader technology. For instance, teniposide potently blocked the human P2X7 at sub-miromolar concentrations, but not human P2X4 or rat P2X2. A marked block of ATPinduced Ca 2+ entry and Yo-Pro-1 uptake was also observed in human A375 melanoma cells and mouse microglial cells, both expressing P2X7. On the other hand, agelasine (AGL) and garcinolic acid (GA) facilitated the P2X7 response to ATP in all three cell populations. GA also enhanced the YO-PRO-1 uptake, whereas AGL did not affect the ATP-stimulated intracellular accumulation of this dye. According to the pathophysiological role of P2X7 in various diseases, selective modulators may have potential for further development, e.g. as neuroprotective or antineoplastic drugs.

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“…pore-opening mechanism | transmembrane intersubunit crevices P 2X receptor channels are a family of trimeric cation-selective channels that are activated by extracellular ATP (1,2). These ligand-gated ion channels are expressed in many tissues, including the central and peripheral nervous systems and the immune system, where they play a range of important roles in sensory signaling and inflammation (1,3).…”

mentioning

confidence: 99%

“…These ligand-gated ion channels are expressed in many tissues, including the central and peripheral nervous systems and the immune system, where they play a range of important roles in sensory signaling and inflammation (1,3).…”

mentioning

confidence: 99%

Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels

Heymann

Dai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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P2X receptor channels open in response to the binding of extracellular ATP, a property that is essential for purinergic sensory signaling. Apo and ATP-bound X-ray structures of the detergentsolubilized zebrafish P2X4 receptor provide a blueprint for receptor mechanisms but unexpectedly showed large crevices between subunits within the transmembrane (TM) domain of the ATPbound structure. Here we investigate both intersubunit and intrasubunit interactions between TM helices of P2X receptors in membranes using both computational and functional approaches. Our results suggest that intersubunit crevices found in the TM domain of the ATP-bound crystal structure are not present in membraneembedded receptors but substantiate helix interactions within individual subunits and identify a hot spot at the internal end of the pore where both the gating and permeation properties of P2X receptors can be tuned. We propose a model for the structure of the open state that has stabilizing intersubunit interactions and that is compatible with available structural constraints from functional channels in membrane environments.pore-opening mechanism | transmembrane intersubunit crevices P 2X receptor channels are a family of trimeric cation-selective channels that are activated by extracellular ATP (1, 2). These ligand-gated ion channels are expressed in many tissues, including the central and peripheral nervous systems and the immune system, where they play a range of important roles in sensory signaling and inflammation (1, 3).Recent X-ray structures of the zebrafish P2X4 (zfP2X4) receptor in apo and ATP-bound forms (Protein Data Bank ID codes 4DW0 and 4DW1, respectively) have revealed the molecular design of these proteins (2, 4, 5) and have provided valuable information on how ATP binding triggers the opening of the transmembrane (TM) pore ( Fig. 1 A and B). ATP binds to a cleft between subunits within the large extracellular domain, inducing cleft closure and an accompanying lateral flexing of the β-sheet connecting the extracellular domain to the TM domain (5). The apo structure of the zfP2X4 receptor reveals that the TM1 helix is positioned peripheral to the TM2 helix and that the TM2 helix occludes the pore at the central axis within the outer half of the membrane (4, 5). In accord with this structure, accessibility studies show that the TM2 helix lines the aqueous pore and that the residues forming the gate are positioned within the occlusion in the apo structure (6-8). Lateral fenestrations within the extracellular domain provide a path for ions to enter and exit the extracellular vestibule positioned above this TM2 occlusion, and these fenestrations are thought to change conformation in response to ATP binding (9, 10). The ATP-bound structure shows that pore opening involves widening of the extracellular vestibule and an iris-like expansion of the pore (5). Intersubunit interactions within the TM domain in the apo structure are limited to the gate region of TM2 (5), and thus the pore expansion observed in the ATP-bound struc...

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Neuromodulation by Extracellular ATP and P2X Receptors in the CNS

Cited by 297 publications

References 210 publications

Comparative study of the P2X gene family in animals and plants

Comparative study of the P2X gene family in animals and plants

Natural compounds with P2X7 receptor-modulating properties

Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels

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