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[[File:Plavix 2007-04-19.jpg|thumb|[[Clopidogrel]] (Plavix), an inhibitor of the [[P2Y12]] receptor, was formerly the second best-selling drug in the world<ref>{{cite journal|last=Doll|first=Jacob|coauthors=Zeitler, Emily; Becker, Richard|title=Generic Clopidogrel|journal=JAMA|date=10 July 2013|volume=310|issue=2|pages=145|doi=10.1001/jama.2013.7155|url=http://jama.jamanetwork.com/article.aspx?articleid=1710467}}</ref> ]] |
[[File:Plavix 2007-04-19.jpg|thumb|[[Clopidogrel]] (Plavix), an inhibitor of the [[P2Y12]] receptor, was formerly the second best-selling drug in the world<ref>{{cite journal|last=Doll|first=Jacob|coauthors=Zeitler, Emily; Becker, Richard|title=Generic Clopidogrel|journal=JAMA|date=10 July 2013|volume=310|issue=2|pages=145|doi=10.1001/jama.2013.7155|url=http://jama.jamanetwork.com/article.aspx?articleid=1710467}}</ref> ]] |
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;Acupuncture |
;Acupuncture |
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Mechanical deformation of the skin by [[acupuncture]] needles results in the release of [[Adenosine triphosphate|ATP]] and [[adenosine]].<ref>{{cite journal|last=Berman|first=Brian M.|coauthors=Langevin, Helene M.; Witt, Claudia M.; Dubner, Ronald|title=Acupuncture for Chronic Low Back Pain|journal=[[New England Journal of Medicine]]|date=29 July 2010|volume=363|issue=5|pages=454–461|doi=10.1056/NEJMct0806114|url=http://www.nejm.org/doi/full/10.1056/NEJMct0806114|quote=Acupuncture also has effects on local tissues, including mechanical stimulation of connective tissue, release of adenosine at the site of needle stimulation, and increases in local blood flow}}</ref><ref>{{cite journal|last=Zhang|first=Ruixin|coauthors=Lao, Lixing; Ren, Ke; Berman, Brian M.|title=Mechanisms of Acupuncture–Electroacupuncture on Persistent Pain|journal=[[Anesthesiology (journal)]]|date=February 2014|volume=120|issue=2|pages=482–503|doi=10.1097/ALN.0000000000000101|pmid=24322588|url=http://journals.lww.com/anesthesiology/Fulltext/2014/02000/Mechanisms_of_Acupuncture_Electroacupuncture_on.35.aspx}}</ref><ref>{{cite book|editor=Masino S, Boison D |author=Sawynok J|work=Adenosine a key link between metabolism and brain activity|publisher=Springer|location=New York, NY|isbn=978-1-4614-3903-5|url=http://link.springer.com/chapter/10.1007/978-1-4614-3903-5_17| title=Chapter 17: Adenosine and Pain |quote=in an elegant series of experiments, adenosine has been implicated as a mediator of acupuncture analgesia|page=352}}</ref><ref>{{cite journal|last=Sawynok|first=J.|title=Topical analgesics for neuropathic pain: Preclinical exploration, clinical validation, future development|journal=European Journal of Pain|date=April 2014|volume=18|issue=4|pages=465–481|doi=10.1002/j.1532-2149.2013.00400.x|url=http://onlinelibrary.wiley.com/doi/10.1002/j.1532-2149.2013.00400.x/full|PMID=24108446|quote=... implication of peripheral adenosine (and nucleotides) in acupuncture analgesia in mice (Goldman et al., 2010) and in humans (Takano et al., 2012)}}</ref> The [[Nociception|anti-nociceptive]] effect of acupuncture is |
Mechanical deformation of the skin by [[acupuncture]] needles results in the release of [[Adenosine triphosphate|ATP]] and [[adenosine]].<ref>{{cite journal|last=Berman|first=Brian M.|coauthors=Langevin, Helene M.; Witt, Claudia M.; Dubner, Ronald|title=Acupuncture for Chronic Low Back Pain|journal=[[New England Journal of Medicine]]|date=29 July 2010|volume=363|issue=5|pages=454–461|doi=10.1056/NEJMct0806114|url=http://www.nejm.org/doi/full/10.1056/NEJMct0806114|quote=Acupuncture also has effects on local tissues, including mechanical stimulation of connective tissue, release of adenosine at the site of needle stimulation, and increases in local blood flow}}</ref><ref>{{cite journal|last=Zhang|first=Ruixin|coauthors=Lao, Lixing; Ren, Ke; Berman, Brian M.|title=Mechanisms of Acupuncture–Electroacupuncture on Persistent Pain|journal=[[Anesthesiology (journal)]]|date=February 2014|volume=120|issue=2|pages=482–503|doi=10.1097/ALN.0000000000000101|pmid=24322588|url=http://journals.lww.com/anesthesiology/Fulltext/2014/02000/Mechanisms_of_Acupuncture_Electroacupuncture_on.35.aspx}}</ref><ref>{{cite book|editor=Masino S, Boison D |author=Sawynok J|work=Adenosine a key link between metabolism and brain activity|publisher=Springer|location=New York, NY|isbn=978-1-4614-3903-5|url=http://link.springer.com/chapter/10.1007/978-1-4614-3903-5_17| title=Chapter 17: Adenosine and Pain |quote=in an elegant series of experiments, adenosine has been implicated as a mediator of acupuncture analgesia|page=352}}</ref><ref>{{cite journal|last=Sawynok|first=J.|title=Topical analgesics for neuropathic pain: Preclinical exploration, clinical validation, future development|journal=European Journal of Pain|date=April 2014|volume=18|issue=4|pages=465–481|doi=10.1002/j.1532-2149.2013.00400.x|url=http://onlinelibrary.wiley.com/doi/10.1002/j.1532-2149.2013.00400.x/full|PMID=24108446|quote=... implication of peripheral adenosine (and nucleotides) in acupuncture analgesia in mice (Goldman et al., 2010) and in humans (Takano et al., 2012)}}</ref> The [[Nociception|anti-nociceptive]] effect of acupuncture is mediated by the [[adenosine A1 receptor]].<ref>{{cite journal|last=Yang|first=Edward S.|coauthors=Li, Pei-Wen; Nilius, Bernd; Li, Geng|title=Ancient Chinese medicine and mechanistic evidence of acupuncture physiology|journal=[[Pflügers Archiv: European Journal of Physiology|European Journal of Physiology]]|quote=Anti-nociceptive effect of acupuncture requires A1 receptors|date=26 August 2011|volume=462|issue=5|pages=645–653|doi=10.1007/s00424-011-1017-3|url=http://link.springer.com/article/10.1007/s00424-011-1017-3/fulltext.html}}</ref><ref>{{cite journal|last=Zylka|first=Mark J.|title=Pain-relieving prospects for adenosine receptors and ectonucleotidases|journal=[[Trends (journals)|Trends in Molecular Medicine]]|date=April 2011|volume=17|issue=4|pages=188–196|doi=10.1016/j.molmed.2010.12.006|url=http://www.sciencedirect.com/science/article/pii/S1471491410001929|quote=Antinociceptive effects of acupuncture require A1R activation}}</ref><ref>{{cite journal|last=Langevin|first=Helene|title=Acupuncture, Connective Tissue, and Peripheral Sensory Modulation|journal=[[Critical Reviews in Eukaryotic Gene Expression]]|doi=10.1615/CritRevEukaryotGeneExpr.2014008284|url=http://www.dl.begellhouse.com/journals/6dbf508d3b17c437,forthcoming,8284.html|accessdate=6 May 2014}}</ref><ref>{{cite journal|last=Giorgi|first=Irene|coauthors=Nieri, Paola|title=Adenosine A1 modulators: a patent update (2008 to present)|journal=''[[Expert Opinion on Therapeutic Patents]]''|date=September 2013|volume=23|issue=9|pages=1109–1121|quote=The role of adenosine in acupuncture-mediated antinociception have been presented by demonstrating the local increase in adenosine concentration in the point receiving traditional acupuncture. Moreover, an A1-mediated effect of adenosine in analgesia by acupuncture has been demonstrated.|doi=10.1517/13543776.2013.799142|url=http://informahealthcare.com/doi/full/10.1517/13543776.2013.799142}}</ref> |
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;Anti-inflammatory drugs |
;Anti-inflammatory drugs |
Revision as of 01:57, 7 May 2014
Part of a series on |
Purinergic signalling |
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Concepts |
Membrane transporters |
Purinergic signalling (or signaling: see American and British English differences) is a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP. It involves the activation of purinergic receptors in the cell and/or in nearby cells, thereby regulating cellular functions.[1]
The purinergic signalling complex of a cell is sometimes referred to as the “purinome”.
Background
Evolutionary origins
Purinergic receptors, represented by several families, are among the most abundant receptors in living organisms and appeared early in evolution.[3]
Among invertebrates, the purinergic signalling system has been found in bacteria, amoeba, ciliates, algae, fungi, anemones, ctenophores, platyhelminthes, nematodes, crustacea, molluscs, annelids, echinoderms, and insects.[4] In green plants, extracellular ATP and other nucleotides induce an increase in the cytosolic concentration of calcium ions, in addition to other downstream changes that influence plant growth and modulate responses to stimuli.[5]
The primitive P2X receptors of unicellular organisms often share low sequence homology with those in mammals, yet they still retain micromolar sensitivity to ATP. The evolution of this receptor class is estimated to have occurred over a billion years ago.[6]
Molecular mechanisms
Generally speaking, all cells have the ability to release nucleotides. In neuronal and neuroendocrinal cells, this mostly occurs via regulated exocytosis.[1] Released nucleotides can be hydrolyzed extracellularly by a variety of cell surface-located enzymes referred to as ectonucleotidases. The purinergic signalling system consists of transporters, enzymes and receptors responsible for the synthesis, release, action, and extracellular inactivation of (primarily) ATP and its extracellular breakdown product adenosine.[7] The signalling effects of uridine triphosphate (UTP) and uridine diphosphate (UDP) are generally comparable to those of ATP.[8]
Purinergic receptors
Purinergic receptors are specific classes of membrane receptors that mediate various physiological functions such as the relaxation of gut smooth muscle, as a response to the release of ATP or adenosine. There are three known distinct classes of purinergic receptors, known as P1, P2X, and P2Y receptors. Cell signalling events initiated by P1 and P2Y receptors have opposing effects in biological systems.[9]
Name | Activation | Class |
P1 receptors | adenosine | G protein-coupled receptors |
P2Y receptors | nucleotides | G protein-coupled receptors |
P2X receptors | ATP | ligand-gated ion channel |
Nucleoside transporters
Nucleoside transporters (NTs) are a group of membrane transport proteins which transport nucleoside substrates including adenosine across the membranes of cells and/or vesicles. NTs are considered to be evolutionarily ancient membrane proteins and are found in many different forms of life.[10] There are two types of NTs:
- Concentrative nucleoside transporters (CNTs): Na+-dependent symporters[10]
- Equilibrative nucleoside transporters (ENTs): Na+-independent passive transporters[10]
The extracellular concentration of adenosine can be regulated by NTs, possibly in the form of a feedback loop connecting receptor signaling with transporter function.[10]
Ectonucleotidases
Released nucleotides can be hydrolyzed extracellularly by a variety of cell surface-located enzymes referred to as ectonucleotidases that control purinergic signalling. Extracellular nucleoside triphosphates and diphosphates are substrates of the ectonucleoside triphosphate diphophohydrolases (E-NTPDases), the ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs) and alkaline phosphatases (APs). Extracellular AMP is hydrolyzed to adenosine by ecto-5'-nucleotidase (eN) as well as by APs. In any case, the final product of the hydrolysis cascade is the nucleoside.[11][12]
Pannexins
The Pannexin-1 channel (PANX1) is an integral component of the P2X/P2Y purinergic signaling pathway and the key contributor to pathophysiological ATP release.[13] For example, the PANX1 channel, along with ATP, purinergic receptors, and ectonucleotidases, contribute to several feedback loops during the inflammatory response.[14]
Purinergic signalling in humans
Circulatory system
In the human heart, adenosine functions as an autacoid in the regulation of various cardiac functions such as heart rate, contractility, and coronary flow. There are currently four types of adenosine receptors found in the heart.[15] After binding onto a specific purinergic receptor, adenosine causes a negative chronotropic effect due to its influence on cardiac pacemakers. It also causes a negative dromotropic effect through the inhibition of AV-nodal conduction.[16] From the 1980s onwards, these effects of adenosine have been used in the treatment of patients with supraventricular tachycardia.[17]
The regulation of vascular tone in the endothelium of blood vessels is mediated by purinergic signalling. A decreased concentration of oxygen releases ATP from erythrocytes, triggering a propagated calcium wave in the endothelial layer of blood vessels and a subsequent production of nitric oxide that results in vasodilation.[18][19]
During the blood clotting process, adenosine diphosphate (ADP) plays a crucial role in the activation and recruitment of platelets and also ensures the structural integrity of thrombi. These effects are modulated by the P2RY1 and the P2Y12 receptors. The P2RY1 receptor is responsible for shape change in platelets, increased intracellular calcium levels and transient platelet aggregation, while the P2Y12 receptor is responsible for sustained platelet aggregation through the inhibition of adenylate cyclase and a corresponding decrease in cyclic adenosine monophosphate (cAMP) levels. The activation of both purinergic receptors is necessary to achieve sustained hemostasis.[20][21]
Digestive system
In the liver, ATP is constantly released during homeostasis and its signalling via P2 receptors influences bile secretion as well as liver metabolism and regeneration.[22] P2Y receptors in the enteric nervous system and at intestinal neuromuscular junctions modulate intestinal secretion and motility.[23]
Endocrine system
Cells of the pituitary gland secrete ATP, which acts on P2Y and P2X purinoreceptors.[24]
Immune system
Autocrine purinergic signalling is an important checkpoint in the activation of white blood cells. These mechanisms either enhance or inhibit cell activation based on the purinergic receptors involved, allowing cells to adjust their functional responses initiated by extracellular evironmental cues.[25]
Like most immunomodulating agents, ATP can act either as an immunosuppressive or an immunostimulatory factor, depending on the cytokine microenviroment and the type of cell receptor.[26] In white blood cells such as macrophages, dendritic cells, lymphocytes, eosinophils, and mast cells, purinergic signalling plays a pathophysiological role in calcium mobilization, actin polymerization, release of mediators, cell maturation, cytotoxicity, and apoptosis.[27] Large increases in extracellular ATP that are associated with cell death serve as a "danger signal" in the inflammatory processes.[28]
In neutrophils, tissue adenosine can either activate or inhibit various neutrophil functions, depending on the inflammatory microenvironment, the expression of adenosine receptors on the neutrophil, and the affinity of these receptors for adenosine. Micromolar concentrations of adenosine activate A2A and A2B receptors. This inhibits the release of granules and prevents oxidative burst. On the other hand, nanomolar concentrations of adenosine activate A1 and A3 receptors, resulting in neutrophilic chemotaxis towards inflammatory stimuli. The release of ATP and an autocrine feedback through P2RY2 and A3 receptors are signal amplifiers.[29][30] Hypoxia-inducible factors also influence adenosine signalling.[17]
Nervous system
In the central nervous system (CNS), ATP is released from synaptic terminals and binds to a plethora of ionotropic and metabotropic receptors. It has an excitatory effect on neurones, and acts as a mediator in neuronal–glial communications.[31] Both adenosine and ATP induce astrocyte cell proliferation. In microglia, P2X and P2Y receptors are expressed. The P2Y6 receptor, which is primarily mediated by uridine diphosphate (UDP), plays a significant role in microglial phagoptosis, while the P2Y12 receptor functions as a specialized pattern recognition receptor. P2RX4 receptors are involved in the CNS mediation of neuropathic pain.[32]
In the peripheral nervous system, Schwann cells respond to nerve stimulation and modulate the release of neurotransmitters through mechanisms involving ATP and adenosine signalling.[33]
During neurogenesis and in early brain development, ectonucleotidases often downregulate purinergic signalling in order to prevent the uncontrolled growth of progenitor cells and to establish a suitable environment for neuronal differentiation.[34]
Renal system
In the kidneys, the glomerular filtration rate (GFR) is regulated by several mechanisms including tubuloglomerular feedback (TGF), in which an increased distal tubular sodium chloride concentration causes a basolateral release of ATP from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level.[35][36]
Respiratory system
ATP and adenosine are crucial regulators of mucociliary clearance.[37] The secretion of mucin involves P2RY2 receptors found on the apical membrane of goblet cells.[37] Extracellular ATP signals acting on glial cells and the neurons of the respiratory rhythm generator contribute to the regulation of breathing.[38]
Skeletal system
In the human skeleton, nearly all P2Y and P2X receptors have been found in osteoblasts and osteoclasts. These receptors enable the regulation of multiple processes such as cell proliferation, differentiation, function, and death.[39] The activation of the adenosine A1 receptor is required for osteoclast differentiation and function, whereas the activation of the adenosine A2A receptor inhibits osteoclast function. The other three adenosine receptors are involved in bone formation.[40]
Pathological aspects
Alzheimer’s disease
In Alzheimer’s disease (AD), the expression of A1 and A2A receptors in the frontal cortex of the human brain is increased, while the expression of A1 receptors in the outer layers of hippocampal dentate gyrus is decreased.[34]
Asthma
In the airways of patients with asthma, the expression of adenosine receptors is upregulated. Adenosine receptors affect bronchial reactivity, endothelial permeability, fibrosis, angiogenesis and mucus production.[41]
Bone diseases
Purinergic signalling is involved in the pathophysiology of several bone and cartilage diseases such as osteoarthritis, rheumatoid arthritis, and osteoporosis.[42] Single-nucleotide polymorphisms (SNPs) in the P2RX7 receptor gene are associated with an increased risk of bone fracture.[39]
Cancer
The P2RX7 receptor is overexpressed in most malignant tumors.[43] The expression of the adenosine A2A receptor on endothelial cells is upregulated in the early stages of human lung cancer.[44]
Cardiovascular diseases
Formation of foam cells is inhibited by adenosine A2A receptors.[45]
Chronic obstructive pulmonary disease
Abnormal levels of ATP and adenosine are present in the airways of patients with chronic obstructive pulmonary disease.[46][47]
Erectile disorders
The release of ATP increases adenosine levels and activates nitric oxide synthase, both of which induces the relaxation of the corpus cavernosum penis. In male patients with vasculogenic impotence, dysfunctional adenosine A2B receptors are associated with the resistance of the corpus cavernosum to adenosine. On the other hand, excess adenosine in penile tissue contributes to priapism.[48][49]
Fibrosis
Persistently elevated concentrations of adenosine beyond the acute-injury phase leads to fibrotic remodelling.[50]
Graft-versus-host disease
Following tissue injury in patients with Graft-versus-host disease (GVHD), ATP is released into the pertioneal fluid. It binds onto the P2RX7 receptors of host antigen-presenting cells (APCs) and activates the inflammasomes. As a result, the expression of co-stimulatory molecules by APCs is upregulated. The inhibition of the P2X7 receptor increases the number of regulatory T cells and decreases the incidence of acute GVHD.[51]
Therapeutic interventions
Current
- Acupuncture
Mechanical deformation of the skin by acupuncture needles results in the release of ATP and adenosine.[53][54][55][56] The anti-nociceptive effect of acupuncture is mediated by the adenosine A1 receptor.[57][58][59][60]
- Anti-inflammatory drugs
Methotrexate, which has strong anti-inflammatory properties, inhibits the action of dihydrofolate reductase, leading to an accumulation of adenosine. On the other hand, the adenosine-receptor antagonist caffeine reverses the anti-inflammatory effects of methotrexate.[61]
- Anti-platelet drugs
Many anti-platelet drugs such as Prasugrel, Ticagrelor, and Ticlopidine are adenosine diphosphate (ADP) receptor inhibitors. Before the expiry of its patent, the P2Y12 receptor antagonist Clopidogrel (trade name: Plavix) was the second most prescribed drug in the world. In 2010 alone, it generated over US$9 billion in global sales.[62]
- Bronchodilators
Theophylline was originally used as a bronchodilator, although its usage has declined due to several side effects such as seizures and cardiac arrhythmias caused by adenosine A1 receptor antagonism.[63]
- Herbal medicine
Several herbs used in Traditional Chinese medicine contain drug compounds that are antagonists of P2X purinoreceptors.[64] The following table provides an overview of these drug compounds and their interaction with purinergic receptors.
Herb | Drug compound | Physiologic effects on purinergic receptors |
Ligustrazine |
| |
Ligusticum wallichii |
| |
Radix puerariae | ||
Rheum officinale | ||
Rhubarb |
- Vasodilators
Regadenoson, a vasodilator which acts on the adenosine A2A receptor, was approved by the United States Food and Drug Administration in 2008 and is currently widely used in the field of cardiology.[72][73] Both adenosine and dipyridamole, which act on the A2A receptor, are used in myocardial perfusion imaging.[74]
Proposed
Purinergic signalling is an important regulatory mechanism in a wide range of inflammatory diseases. It is understood that shifting the balance between purinergic P1 and P2 signalling is an emerging therapeutic concept that aims to dampen pathologic inflammation and promote healing.[9] The following list of proposed medications is based on the workings of the purinergic signalling system:
- Diquafosol - Agonist of the P2Y2 receptor used in the treatment of dry eye disease.[75]
- Istradefylline - Antagonist of the adenosine A2A receptor, used in the treatment of Parkinson's disease as an adjunct to L-DOPA.[76]
History
The earliest reports of purinergic signalling date back to 1929, when the Hungarian physiologist Albert Szent-Györgyi observed that purified adenine compounds produced a temporary reduction in heart rate when injected into animals.[9][77]
In the 1960s, the classical view of autonomic smooth muscle control was based upon Dale's principle, which asserts that each nerve cell can synthesize, store, and release only one neurotransmitter. It was therefore assumed that a sympathetic neuron releases noradrenaline only, while an antagonistic parasympathetic neuron releases acetylcholine only. Although the concept of cotransmission gradually gained acceptance in the 1980s, the belief that a single neuron acts via a single type of neurotransmitter continued to dominate the field of neurotransmission throughout the 1970s.[78]
Beginning in 1972, Geoffrey Burnstock ignited decades of controversy after he proposed the existence of a non-adrenergic, non-cholinergic (NANC) neurotransmitter, which he identified as ATP after observing the cellular responses in a number of systems exposed to the presence of cholinergic and adrenergic blockers.[79][80][81]
Burnstock's proposal was met with criticism, since ATP is an ubiquitous intracellular molecular energy source[82] so it seemed counter-intuitive that cells might also actively release this vital molecule as a neurotransmitter. After years of prolonged scepticism, however, the concept of purinergic signalling was gradually accepted by the scientific community.[1]
Today, purinergic signalling is no longer considered to be confined to neurotransmission, but is regarded as a general intercellular communication system of many, if not all, tissues.[1]
See also
References
- ^ a b c d Praetorius, Helle A. (1 March 2010). "Intrarenal Purinergic Signaling in the Control of Renal Tubular Transport". Annual Review of Physiology. 72 (1): 377–393. doi:10.1146/annurev-physiol-021909-135825. PMID 20148681.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Tanaka, Kiwamu (October 2010). "Extracellular ATP signaling in plants". Trends in Cell Biology. 20 (10): 601–608. doi:10.1016/j.tcb.2010.07.005.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Abbracchio, Maria P. (2009). "Purinergic signalling in the nervous system: an overview". Trends in Neurosciences. 32 (1): 19–29. doi:10.1016/j.tins.2008.10.001. PMID 19008000.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Burnstock, G. (1 April 2009). "Evolutionary origins of the purinergic signalling system". Acta Physiologica. 195 (4): 415–447. doi:10.1111/j.1748-1716.2009.01957.x.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Roux, Stanley J. (November 2007). "Extracellular ATP: an unexpected role as a signaler in plants". Trends in Plant Science. 12 (11): 522–527. doi:10.1016/j.tplants.2007.09.003.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Fountain, Samuel J. (2013). "Primitive ATP-activated P2X receptors: discovery, function and pharmacology". Frontiers in Cellular Neuroscience. 7. doi:10.3389/fncel.2013.00247.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ Sperlagh, B (December 2012). "The role of purinergic signaling in depressive disorders". Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology. 14 (4): 231–8. PMID 23269209.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Corriden, R. (5 January 2010). "Basal Release of ATP: An Autocrine-Paracrine Mechanism for Cell Regulation". Science Signaling. 3 (104): re1–re1. doi:10.1126/scisignal.3104re1.
Cells release other nucleotides [for example, uridine triphosphate (UTP) and related molecules such as uridine diphosphate (UDP) sugars] that have actions akin to those of ATP
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ a b c Eltzschig, Holger K. (13 December 2012). "Purinergic Signaling during Inflammation". New England Journal of Medicine. 367 (24): 2322–2333. doi:10.1056/NEJMra1205750.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ a b c d dos Santos-Rodrigues, Alexandre (April 2014). "Nucleoside transporters in the purinome". Neurochemistry International. doi:10.1016/j.neuint.2014.03.014.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Jacobson, edited by Kenneth A. (2011). Pharmacology of Purine and Pyrimidine Receptors (1st ed. ed.). Amsterdam: Elsevier/Academic Press. pp. 301–332. ISBN 0123855268.
{{cite book}}
:|edition=
has extra text (help);|first=
has generic name (help); Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Zimmermann, H. (2012). "Cellular function and molecular structure of ecto-nucleotidases". Purinergic Signalling. 8 (3): 437–502. doi:10.1007/s11302-012-9309-4.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Makarenkova, Helen P. (2014). "The role of pannexin hemichannels in inflammation and regeneration". Frontiers in Physiology. 5. doi:10.3389/fphys.2014.00063.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ Adamson, Samantha E. (April 2014). "The role of pannexin1 in the induction and resolution of inflammation". FEBS Letters. 588 (8): 1416–1422. doi:10.1016/j.febslet.2014.03.009.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ McIntosh, V. J. (18 February 2011). "Adenosine Receptor-Mediated Cardioprotection: Are All 4 Subtypes Required or Redundant?". Journal of Cardiovascular Pharmacology and Therapeutics. 17 (1): 21–33. doi:10.1177/1074248410396877.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Mustafa, SJ (2009). "Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology". Handbook of Experimental Pharmacology (193): 161–88. PMID 19639282.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ a b Colgan, Sean P. (17 March 2012). "Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery". Annual Review of Physiology. 74 (1): 153–175. doi:10.1146/annurev-physiol-020911-153230.
{{cite journal}}
: Italic or bold markup not allowed in:|journal=
(help); Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Lohman, A. W. (7 June 2012). "Mechanisms of ATP release and signalling in the blood vessel wall". Cardiovascular Research. 95 (3): 269–280. doi:10.1093/cvr/cvs187.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Dahl, Gerhard (March 2014). "Innexin and pannexin channels and their signaling". FEBS Letters. doi:10.1016/j.febslet.2014.03.007.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Storey, R. F. (7 July 2011). "New P2Y12 inhibitors". Heart. 97 (15): 1262–1267. doi:10.1136/hrt.2009.184242.
- ^ Barn, Kulpreet (September 2012). "A brief review of the past and future of platelet P2Y12 antagonist". Coronary Artery Disease. 23 (6): 368–374. doi:10.1097/MCA.0b013e3283564930. PMID 22735090.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Oliveira, André G. (March 2013). "Purinergic signalling during sterile liver injury". Liver International. 33 (3): 353–361. doi:10.1111/liv.12109.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Wood, JD (December 2006). "The enteric purinergic P2Y1 receptor". Current Opinion in Pharmacology. 6 (6): 564–570. doi:10.1016/j.coph.2006.06.006. PMID 16934527.
- ^ Stojilkovic, Stanko S (July 2001). "Signaling by extracellular nucleotides in anterior pituitary cells". Trends in Endocrinology & Metabolism. 12 (5): 218–225. doi:10.1016/S1043-2760(01)00387-3.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Junger, Wolfgang G. (18 February 2011). "Immune cell regulation by autocrine purinergic signalling". Nature Reviews Immunology. 11 (3): 201–212. doi:10.1038/nri2938.
- ^ "Final Report Summary - ATPBONE (Fighting osteoporosis by blocking nucleotides: purinergic signalling in bone formation and homeostasis)". CORDIS. Retrieved 4 September 2013.
- ^ Jacob, Fenila (2013). "Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses". Purinergic Signalling. 9 (3): 285–306. doi:10.1007/s11302-013-9357-4. PMID 23404828.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Trautmann, A. (3 February 2009). "Extracellular ATP in the Immune System: More Than Just a "Danger Signal"". Science Signaling. 2 (56): pe6–pe6. doi:10.1126/scisignal.256pe6.
- ^ Barletta, K. E. (8 June 2012). "Regulation of Neutrophil Function by Adenosine". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (4): 856–864. doi:10.1161/atvbaha.111.226845. PMID 22423037.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Eltzschig, Holger K. (April 2008). "Neutrophils as Sources of Extracellular Nucleotides: Functional Consequences at the Vascular Interface". Trends in Cardiovascular Medicine. 18 (3): 103–107. doi:10.1016/j.tcm.2008.01.006.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ North, R. Alan (11 May 2006). "Purinergic transmission in the central nervous system". Pflügers Archiv - European Journal of Physiology. 452 (5): 479–485. doi:10.1007/s00424-006-0060-y.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Ransohoff, Richard M. (April 2009). "Microglial Physiology: Unique Stimuli, Specialized Responses". Annual Review of Immunology. 27 (1): 119–145. doi:10.1146/annurev.immunol.021908.132528.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Fields, R. Douglas (June 2006). "Purinergic signalling in neuron–glia interactions". Nature Reviews Neuroscience. 7 (6): 423–436. doi:10.1038/nrn1928.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ a b Puerto, Ana del (2013). "Neuronal and glial purinergic receptors functions in neuron development and brain disease". Frontiers in Cellular Neuroscience. 7. doi:10.3389/fncel.2013.00197.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ Arulkumaran, Nishkantha (1 January 2013). "Purinergic signaling in inflammatory renal disease". Frontiers in Physiology. 4. doi:10.3389/fphys.2013.00194. PMC 3725473.
Extracellular adenosine contributes to the regulation of GFR. Renal interstitial adenosine is mainly derived from dephosphorylation of released ATP, AMP, or cAMP by the enzyme ecto-5′-nucleotidase (CD73) (Le Hir and Kaissling, 1993). This enzyme catalyzes the dephosphorylation of 5′-AMP or 5′-IMP to adenosine or inosine, respectively, and is located primarily on the external membranes and mitochondria of proximal tubule cells, but not in distal tubule or collecting duct cells (Miller et al., 1978). ATP consumed in active transport by the macula densa also contributes to the formation of adenosine by 5- nucleotidase (Thomson et al., 2000). Extracellular adenosine activates A1 receptors on vascular afferent arteriolar smooth muscle cells, resulting in vasoconstriction and a reduction in GFR (Schnermann et al., 1990).
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ REN, YILIN (1 October 2004). "Role of macula densa adenosine triphosphate (ATP) in tubuloglomerular feedback". Kidney International. 66 (4): 1479–1485. doi:10.1111/j.1523-1755.2004.00911.x.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ a b Lazarowski, Eduardo R (June 2009). "Purinergic receptors in airway epithelia". Current Opinion in Pharmacology. 9 (3): 262–267. doi:10.1016/j.coph.2009.02.004.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Housley, Gary D. (October 2011). "Recent insights into the regulation of breathing". Autonomic Neuroscience. 164 (1–2): 3–5. doi:10.1016/j.autneu.2011.08.002.
- ^ a b Rumney, Robin M. H. (2012). "Purinergic signalling in bone". Frontiers in Endocrinology. 3. doi:10.3389/fendo.2012.00116.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ Mediero, Aránzazu (June 2013). "Adenosine and bone metabolism". Trends in Endocrinology & Metabolism. 24 (6): 290–300. doi:10.1016/j.tem.2013.02.001.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Wilson, C N (29 January 2009). "Adenosine receptors and asthma in humans". British Journal of Pharmacology. 155 (4): 475–486. doi:10.1038/bjp.2008.361.
- ^ Jørgensen, Niklas Rye (1 January 2013). "Purinergic Signaling in Bone". Journal of Osteoporosis. 2013: 1–2. doi:10.1155/2013/673684.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ Di Virgilio, F. (22 October 2012). "Purines, Purinergic Receptors, and Cancer". Cancer Research (Editorial). 72 (21): 5441–5447. doi:10.1158/0008-5472.CAN-12-1600.
- ^ Antonioli, Luca (14 November 2013). "Immunity, inflammation and cancer: a leading role for adenosine". Nature Reviews Cancer. 13 (12): 842–857. doi:10.1038/nrc3613.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Reiss, A. B. (8 June 2012). "Regulation of Foam Cells by Adenosine". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (4): 879–886. doi:10.1161/atvbaha.111.226878.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Mortaz, Esmaeil (July 2010). "ATP and the pathogenesis of COPD". European Journal of Pharmacology. 638 (1–3): 1–4. doi:10.1016/j.ejphar.2010.04.019.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Esther CR, Jr (2011). "Regulation of airway nucleotides in chronic lung diseases". Sub-cellular biochemistry. 55: 75–93. doi:10.1007/978-94-007-1217-1_4. PMID 21560045.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Phatarpekar, Prasad V. (November 2010). "Role of Adenosine Signaling in Penile Erection and Erectile Disorders". The Journal of Sexual Medicine. 7 (11): 3553–3564. doi:10.1111/j.1743-6109.2009.01555.x.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Wen, J. (8 June 2012). "Adenosine Signaling: Good or Bad in Erectile Function?". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (4): 845–850. doi:10.1161/atvbaha.111.226803. PMID 22423035.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Karmouty-Quintana, Harry (23 January 2013). "Adenosine signaling during acute and chronic disease states". Journal of Molecular Medicine. 91 (2): 173–181. doi:10.1007/s00109-013-0997-1.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Blazar, Bruce R. (11 May 2012). "Advances in graft-versus-host disease biology and therapy". Nature Reviews Immunology. 12 (6): 443–458. doi:10.1038/nri3212.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Doll, Jacob (10 July 2013). "Generic Clopidogrel". JAMA. 310 (2): 145. doi:10.1001/jama.2013.7155.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Berman, Brian M. (29 July 2010). "Acupuncture for Chronic Low Back Pain". New England Journal of Medicine. 363 (5): 454–461. doi:10.1056/NEJMct0806114.
Acupuncture also has effects on local tissues, including mechanical stimulation of connective tissue, release of adenosine at the site of needle stimulation, and increases in local blood flow
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Zhang, Ruixin (February 2014). "Mechanisms of Acupuncture–Electroacupuncture on Persistent Pain". Anesthesiology (journal). 120 (2): 482–503. doi:10.1097/ALN.0000000000000101. PMID 24322588.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Sawynok J. Masino S, Boison D (ed.). Chapter 17: Adenosine and Pain. New York, NY: Springer. p. 352. ISBN 978-1-4614-3903-5.
in an elegant series of experiments, adenosine has been implicated as a mediator of acupuncture analgesia
{{cite book}}
:|work=
ignored (help) - ^ Sawynok, J. (April 2014). "Topical analgesics for neuropathic pain: Preclinical exploration, clinical validation, future development". European Journal of Pain. 18 (4): 465–481. doi:10.1002/j.1532-2149.2013.00400.x. PMID 24108446.
... implication of peripheral adenosine (and nucleotides) in acupuncture analgesia in mice (Goldman et al., 2010) and in humans (Takano et al., 2012)
- ^ Yang, Edward S. (26 August 2011). "Ancient Chinese medicine and mechanistic evidence of acupuncture physiology". European Journal of Physiology. 462 (5): 645–653. doi:10.1007/s00424-011-1017-3.
Anti-nociceptive effect of acupuncture requires A1 receptors
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Zylka, Mark J. (April 2011). "Pain-relieving prospects for adenosine receptors and ectonucleotidases". Trends in Molecular Medicine. 17 (4): 188–196. doi:10.1016/j.molmed.2010.12.006.
Antinociceptive effects of acupuncture require A1R activation
- ^ Langevin, Helene. "Acupuncture, Connective Tissue, and Peripheral Sensory Modulation". Critical Reviews in Eukaryotic Gene Expression. doi:10.1615/CritRevEukaryotGeneExpr.2014008284. Retrieved 6 May 2014.
- ^ Giorgi, Irene (September 2013). "Adenosine A1 modulators: a patent update (2008 to present)". Expert Opinion on Therapeutic Patents. 23 (9): 1109–1121. doi:10.1517/13543776.2013.799142.
The role of adenosine in acupuncture-mediated antinociception have been presented by demonstrating the local increase in adenosine concentration in the point receiving traditional acupuncture. Moreover, an A1-mediated effect of adenosine in analgesia by acupuncture has been demonstrated.
{{cite journal}}
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(help); Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Chan, Edwin SL (2002). "Molecular action of methotrexate in inflammatory diseases". Arthritis Research. 4 (4): 266. doi:10.1186/ar419.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ Topol, Eric J (January 2011). "Catapulting clopidogrel pharmacogenomics forward". Nature Medicine. 17 (1): 40–41. doi:10.1038/nm0111-40.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Barnes, Peter J. (15 October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP.
- ^ a b Liang, Shangdong (December 2010). "P2X receptors and modulation of pain transmission: Focus on effects of drugs and compounds used in traditional Chinese medicine". Neurochemistry International. 57 (7): 705–712. doi:10.1016/j.neuint.2010.09.004.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Burnstock, G. (1 March 2006). "Pathophysiology and Therapeutic Potential of Purinergic Signaling". Pharmacological Reviews. 58 (1): 58–86. doi:10.1124/pr.58.1.5.
Tetramethylpyrazine, a traditional Chinese medicine used as an analgesic for dysmenorrhea, was shown to block P2X3 receptor signaling
- ^ Burnstock, Geoffrey (June 2006). "Purinergic P2 receptors as targets for novel analgesics". Pharmacology & Therapeutics. 110 (3): 433–454. doi:10.1016/j.pharmthera.2005.08.013.
- ^ Burnstock, Geoffrey (8 December 2011). "Purinergic Signaling in Healthy and Diseased Skin". Journal of Investigative Dermatology. 132 (3): 526–546. doi:10.1038/jid.2011.344.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Zhou, Yan-Xi (December 2013). "Puerarin: A Review of Pharmacological Effects". Phytotherapy Research: n/a–n/a. doi:10.1002/ptr.5083.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Jiang, Lin-Hua (2013). "Insights into the Molecular Mechanisms Underlying Mammalian P2X7 Receptor Functions and Contributions in Diseases, Revealed by Structural Modeling and Single Nucleotide Polymorphisms". Frontiers in Pharmacology. 4. doi:10.3389/fphar.2013.00055.
Natural compounds isolated from plants used in traditional medicines have also been shown to selectively inhibit the P2X7Rs
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ Adinolfi, Elena (22 November 2013). "New intriguing roles of ATP and its receptors in promoting tumor metastasis". Purinergic Signalling (journal). 9 (4): 487–490. doi:10.1007/s11302-013-9401-4.
The study from Jelassi and colleagues further support these findings showing the efficacy of emodin, a Chinese traditional medicine compound, in reducing P2X7 mediated malignant progression.
- ^ Burnstock, G (2013 Dec). "Purinergic signalling and cancer". Purinergic Signalling (journal). 9 (4): 491–540. PMID 23797685.
Chrysophanol, a member of the anthraquinone family that is one of the components of a Chinese herb including rhubarb recommended for the treatment of cancer, induces necrosis of J5 human liver cancer cells via reduction in ATP levels
{{cite journal}}
: Check date values in:|date=
(help); Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Chen, Jiang-Fan (28 March 2013). "Adenosine receptors as drug targets — what are the challenges?". Nature Reviews Drug Discovery. 12 (4): 265–286. doi:10.1038/nrd3955.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Palani, Gurunanthan (2013). "Regadenoson". Cardiology in Review. 21 (1): 42–48. doi:10.1097/CRD.0b013e3182613db6.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Cerqueira, Manuel D (July 2004). "The future of pharmacologic stress: selective a2a adenosine receptor agonists". The American Journal of Cardiology. 94 (2): 33–40. doi:10.1016/j.amjcard.2004.04.017.
- ^ Skalicky, Simon (January 2014). "P2Y2 receptor agonists for the treatment of dry eye disease: a review". Clinical Ophthalmology: 327. doi:10.2147/OPTH.S39699.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help)CS1 maint: unflagged free DOI (link) - ^ Chen, Wanqiang (January 2013). "Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: A meta-analysis". Journal of the Neurological Sciences. 324 (1–2): 21–28. doi:10.1016/j.jns.2012.08.030.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Drury AN, Szent-Györgyi A (1929). "The physiological activity of adenine compounds with special reference to their effect on the mammalian heart". J. Physiol. 68 (3): 213–37. PMID 16994064.
- ^ Campbell, G (April 1987). "Cotransmission". Annual Review of Pharmacology and Toxicology. 27 (1): 51–70. doi:10.1146/annurev.pa.27.040187.000411.
- ^ Martinson J, Muren A (1963). "Excitatory and inhibitory effects if vagus stimulation on gastric motility in the cat". Acta Physiol. Scand. 57.
- ^ Burnstock G, Campbell G, Bennett M, Holman ME (1963). "Inhibition of the smooth muscle of the taenia coli". Nature. 200: 581–2. doi:10.1038/200581a0. PMID 14082235.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Burnstock G (1972). "Purinergic Nerves". Pharmacol. Rev. 24 (3): 509–81. PMID 4404211.
- ^ Lipmann F. (1941) Adv. Enzymol. 1, 99-162.