Evolution of P2X receptors

Burnstock, Geoffrey; Verkhratsky, Alexei

doi:10.1002/wmts.13

Cited by 9 publications

(9 citation statements)

References 116 publications

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“…In addition to the GluCl channels, helminths also contain excitatory glutamate-gated cation channels, which play critical roles in the neuromusculature of animals. Interestingly, though schistosomes have functional (Ca 2+ -permeable) P2X channels, nematodes apparently do not [61]. P2X channels act as receptors for extracellular ATP- and adenosine-mediated signaling, with roles in neurotransmission and intercellular signaling in a variety of tissues and organisms.…”

Section: Other Ligand-gated Channelsmentioning

confidence: 99%

Ion Channels and Drug Transporters as Targets for Anthelmintics

Greenberg

2014

Curr Clin Micro Rpt

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Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

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Section: Other Ligand-gated Channelsmentioning

confidence: 99%

Ion Channels and Drug Transporters as Targets for Anthelmintics

Greenberg

2014

Curr Clin Micro Rpt

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“…P2RX7 is a 595aa protein belonging to the ionotropic purinergic P2X subfamily which consists of seven members, P2X1-7 (Burnstock and Knight, 2004 ). P2Xs represent an ancient form of purine chemical messenger reception, with relatives now cloned from species as diverse as Homo sapiens and Dictyostelium (Burnstock and Verkhratsky, 2012 ). All family members are trimeric ligand-gated ion channels displaying a preference for cations.…”

Section: Introductionmentioning

confidence: 99%

P2RX7 Purinoceptor as a Therapeutic Target—The Second Coming?

Young

Górecki²

2018

Front. Chem.

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The P2RX7 receptor is a unique member of a family of extracellular ATP (eATP)-gated ion channels expressed in immune cells, where its activation triggers the inflammatory cascade. Therefore, P2RX7 has been long investigated as a target in the treatment of infectious and inflammatory diseases. Subsequently, P2RX7 signaling has been documented in other physiological and pathological processes including pain, CNS and psychiatric disorders and cancer. As a result, a range of P2RX7 antagonists have been developed and trialed. Interestingly, the recent crystallization of mammalian and chicken receptors revealed that most widely-used antagonists may bind a unique allosteric site. The availability of crystal structures allows rational design of improved antagonists and modeling of binding sites of the known or presumed inhibitors. However, several unanswered questions limit the cogent development of P2RX7 therapies. Firstly, this receptor functions as an ion channel, but its chronic stimulation by high eATP causes opening of the non-selective large pore (LP), which can trigger cell death. Not only the molecular mechanism of LP opening is still not fully understood but its function(s) are also unclear. Furthermore, how can tumor cells take advantage of P2RX7 for growth and spread and yet survive overexpression of potentially cytotoxic LP in the eATP-rich environment? The recent discovery of the feedback loop, wherein the LP-evoked release of active MMP-2 triggers the receptor cleavage, provided one explanation. Another mechanism might be that of cancer cells expressing a structurally altered P2RX7 receptor, devoid of the LP function. Exploiting such mechanisms should lead to the development of new, less toxic anticancer treatments. Notably, targeted inhibition of P2RX7 is crucial as its global blockade reduces the immune and inflammatory responses, which have important anti-tumor effects in some types of malignancies. Therefore, another novel approach is the synthesis of tissue/cell specific P2RX7 antagonists. Progress has been aided by the development of p2rx7 knockout mice and new conditional knock-in and knock-out models are being created. In this review, we seek to summarize the recent advances in our understanding of molecular mechanisms of receptor activation and inhibition, which cause its re-emergence as an important therapeutic target. We also highlight the key difficulties affecting this development.

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“…Seven P2X receptor subunits have been identified. P2X receptors have been cloned from many eukaryotic species, including mammals, fish, parasitic trematode worms, amoeba, slime mould, and green algae (see Fountain and Burnstock, 2009 ; Burnstock and Verkhratsky, 2012a ). The physiology and pathophysiology of P2X receptors in diseases of the special senses, urinary tract, gastrointestinal tract, pancreas, skin, and musculoskeletal system, as well as in cancer and inflammatory disorders will be discussed.…”

Section: Introductionmentioning

confidence: 99%

Introduction and perspective, historical note

Burnstock

2013

Front. Cell. Neurosci.

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P2 nucleotide receptors were proposed to consist of two subfamilies based on pharmacology in 1985, named P2X and P2Y receptors. Later, this was confirmed following cloning of the receptors for nucleotides and studies of transduction mechanisms in the early 1990s. P2X receptors are ion channels and seven subtypes are recognized that form trimeric homomultimers or heteromultimers. P2X receptors are involved in neuromuscular and synaptic neurotransmission and neuromodulation. They are also expressed on many types of non-neuronal cells to mediate smooth muscle contraction, secretion, and immune modulation. The emphasis in this review will be on the pathophysiology of P2X receptors and therapeutic potential of P2X receptor agonists and antagonists for neurodegenerative and inflammatory disorders, visceral and neuropathic pain, irritable bowel syndrome, diabetes, kidney failure, bladder incontinence and cancer, as well as disorders if the special senses, airways, skin, cardiovascular, and musculoskeletal systems.

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Evolution of P2X receptors

Cited by 9 publications

References 116 publications

Ion Channels and Drug Transporters as Targets for Anthelmintics

Ion Channels and Drug Transporters as Targets for Anthelmintics

P2RX7 Purinoceptor as a Therapeutic Target—The Second Coming?

Introduction and perspective, historical note

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