Purinergic receptor

{{short description|Family of cell membrane receptors in almost all tissues}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Purinergic signalling}} '''Purinergic receptors''', also known as '''purinoceptors''', are a family of plasma membrane molecules that are found in almost all mammalian tissues.<ref name="ReferenceA">{{cite journal | vauthors = North RA | title = Molecular physiology of P2X receptors | journal = Physiological Reviews | volume = 82 | issue = 4 | pages = 1013–1067 | date = October 2002 | pmid = 12270951 | doi = 10.1152/physrev.00015.2002 }}</ref> Within the field of purinergic signalling, these receptors have been implicated in learning and memory, locomotor and feeding behavior, and sleep.<ref name="Burnstock_2013">{{cite book | vauthors = Burnstock G | chapter = Introduction to Purinergic Signalling in the Brain | doi = 10.1007/978-94-007-4719-7_1 | title = Glioma Signaling | series = Advances in Experimental Medicine and Biology | volume = 986 | pages = 1–12 | year = 2013 | isbn = 978-94-007-4718-0 | pmid = 22879061 }}</ref> More specifically, they are involved in several cellular functions, including proliferation and migration of neural stem cells, vascular reactivity, apoptosis and cytokine secretion.<ref name="Burnstock_2013" /><ref>{{cite journal | vauthors = Ulrich H, Abbracchio MP, Burnstock G | title = Extrinsic purinergic regulation of neural stem/progenitor cells: implications for CNS development and repair | journal = Stem Cell Reviews and Reports | volume = 8 | issue = 3 | pages = 755–767 | date = September 2012 | pmid = 22544361 | doi = 10.1007/s12015-012-9372-9 | s2cid = 10616782 }}</ref> These functions have not been well characterized and the effect of the extracellular microenvironment on their function is also poorly understood.

Geoff Burnstock originally separated purinoceptors into P1 adenosine receptors and P2 nucleotide (ATP, ADP) receptors.<ref name="Burnstock_2014">{{cite journal | vauthors = Burnstock G | title = Purinergic signalling: from discovery to current developments | journal = Experimental Physiology | volume = 99 | issue = 1 | pages = 16–34 | date = January 2014 | pmid = 24078669 | pmc = 4208685 | doi = 10.1113/expphysiol.2013.071951 }}</ref> P2 receptors were later subdivided into P2X, P2Y, P2T, and P2Z receptors.<ref>{{cite journal | vauthors = Gordon JL | title = Extracellular ATP: effects, sources and fate | journal = The Biochemical Journal | volume = 233 | issue = 2 | pages = 309–319 | date = January 1986 | pmid = 3006665 | pmc = 1153029 | doi = 10.1042/bj2330309 }}</ref> Subclasses X and Y mediated vasoconstriction and vasodilation, respectively, in the smooth muscle of some arteries. They had been observed in blood vessels, smooth muscle, heart, hepatocytes, and parotid acinar cells. Subclass T was only observed in thrombocytes, platelets and megakaryocytes. Subclass Z required ~100 μM-ATP for activation, where the previous classes required <1 μM. They had been observed in mast cells and lymphocytes.

In the early 1990s, purinoceptors were cloned and characterized, and the P2 subclasses were redefined.<ref name="Burnstock_2014" /> Now, P2 receptors are classified based on structure: P2X are ionotropic and P2Y are metabotropic. Appropriately, P2Z was reclassified as P2X7<ref>{{cite journal | vauthors = Surprenant A, Rassendren F, Kawashima E, North RA, Buell G | title = The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7) | journal = Science | volume = 272 | issue = 5262 | pages = 735–738 | date = May 1996 | pmid = 8614837 | doi = 10.1126/science.272.5262.735 }}</ref> and P2T was reclassified as P2Y1.<ref>{{cite journal | vauthors = Léon C, Hechler B, Vial C, Leray C, Cazenave JP, Gachet C | title = The P2Y1 receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells | journal = FEBS Letters | volume = 403 | issue = 1 | pages = 26–30 | date = February 1997 | pmid = 9038354 | doi = 10.1016/S0014-5793(97)00022-7 | bibcode = 1997FEBSL.403...26L }}</ref>

== 3 classes of purinergic receptors == {| class="wikitable" ! Name !! Activation !! Class |- | P1 receptors || adenosine || G protein-coupled receptors |- | P2Y receptors || nucleotides * ATP * ADP * UTP * UDP * UDP-glucose || G protein-coupled receptors |- | P2X receptors || ATP || ligand-gated ion channel |}

There are three known distinct classes of purinergic receptors, known as P1, P2X, and P2Y receptors.

== P2X receptors == {{main|P2X purinoreceptor}} P2X receptors are ligand-gated ion channels, whereas the P1 and P2Y receptors are G protein-coupled receptors. These ligand-gated ion channels are nonselective cation channels responsible for mediating excitatory postsynaptic responses, similar to nicotinic and ionotropic glutamate receptors.<ref>{{cite journal | vauthors = Kaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A | title = Molecular and functional properties of P2X receptors--recent progress and persisting challenges | journal = Purinergic Signalling | volume = 8 | issue = 3 | pages = 375–417 | date = September 2012 | pmid = 22547202 | pmc = 3360091 | doi = 10.1007/s11302-012-9314-7 }}</ref> P2X receptors are distinct from the rest of the widely known ligand-gated ion channels, as the genetic encoding of these particular channels indicates the presence of only two transmembrane domains within the channels.<ref name="ReferenceA" /> These receptors are greatly distributed in neurons and glial cells throughout the central and peripheral nervous systems.<ref name="ReferenceA" /> P2X receptors mediate a large variety of responses including fast transmission at central synapses, contraction of smooth muscle cells, platelet aggregation, macrophage activation, and apoptosis.<ref name="Burnstock_2013" /><ref>{{cite journal | vauthors = Burnstock G, Fredholm BB, North RA, Verkhratsky A | title = The birth and postnatal development of purinergic signalling | journal = Acta Physiologica | volume = 199 | issue = 2 | pages = 93–147 | date = June 2010 | pmid = 20345419 | doi = 10.1111/j.1748-1716.2010.02114.x | s2cid = 25734771 }}</ref> Moreover, these receptors have been implicated in integrating functional activity between neurons, glial, and vascular cells in the central nervous system, thereby mediating the effects of neural activity during development, neurodegeneration, inflammation, and cancer.<ref name="Burnstock_2013" /> The physiological modulator Zn2+ allosterically enhances ATP-induced inward cation currents in the P2X4 receptor by binding to cysteine 132 and cystine 149 residues on the extracellular domain of the P2X4 protein.<ref>{{cite journal | vauthors = Acuña-Castillo C, Morales B, Huidobro-Toro JP | title = Zinc and copper modulate differentially the P2X4 receptor | journal = Journal of Neurochemistry | volume = 74 | issue = 4 | pages = 1529–1537 | date = April 2000 | pmid = 10737610 | doi = 10.1046/j.1471-4159.2000.0741529.x | s2cid = 19142246 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Zemkova H | title = Special Issue of International Journal of Molecular Sciences (IJMS) "Purinergic P2 Receptors: Structure and Function" | journal = International Journal of Molecular Sciences | volume = 22 | issue = 1 | page = 383 | date = December 2020 | pmid = 33396540 | pmc = 7796286 | doi = 10.3390/ijms22010383 | doi-access = free }}</ref>

== P2Y and P1 receptors == Both of these metabotropic receptors are distinguished by their reactivity to specific activators. P1 receptors are preferentially activated by adenosine and P2Y receptors are preferentially more activated by ATP. P1 and P2Y receptors are known to be widely distributed in the brain, heart, kidneys, and adipose tissue. Xanthines (e.g. caffeine) specifically block adenosine receptors, and are known to induce a stimulating effect to one's behavior.<ref>{{cite book | title = Neuroscience | edition = 2nd | veditors = Purves D, Augustine GJ, Fitzpatrick D, Katz L, LaMantia AS, McNamara J, Williams SM | location = Sunderland (MA) | publisher = Sinauer Associates | date = 2001 | isbn = 0-87893-742-0 }}</ref>

== Inhibitors == Inhibitors of purinergic receptors include clopidogrel, prasugrel and ticlopidine, as well as ticagrelor. All of these are antiplatelet agents that block P2Y12 receptors.

== Effects on chronic pain == Data obtained from using P2 receptor-selective antagonists has produced evidence supporting ATP's ability to initiate and maintain chronic pain states after exposure to noxious stimuli. It is believed that ATP functions as a pronociceptive neurotransmitter, acting at specific P2X and P2Y receptors in a systemized manner, which ultimately (as a response to noxious stimuli) serve to initiate and sustain heightened states of neuronal excitability. This recent knowledge of purinergic receptors' effects on chronic pain provide promise in discovering a drug that specifically targets individual P2 receptor subtypes. While some P2 receptor-selective compounds have proven useful in preclinical trials, more research is required to understand the potential viability of P2 receptor antagonists for pain.<ref>{{cite journal | vauthors = Jarvis MF | title = The neural-glial purinergic receptor ensemble in chronic pain states | journal = Trends in Neurosciences | volume = 33 | issue = 1 | pages = 48–57 | date = January 2010 | pmid = 19914722 | doi = 10.1016/j.tins.2009.10.003 | s2cid = 26035589 }}</ref>

Recent research has identified a role for microglial P2X receptors in neuropathic pain and inflammatory pain, especially the P2X4 and P2X7 receptors.<ref>{{cite journal | vauthors = Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K | title = Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays | journal = Molecular Pain | volume = 5 | page = 28 | date = June 2009 | pmid = 19515262 | pmc = 2704200 | doi = 10.1186/1744-8069-5-28 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ulmann L, Hirbec H, Rassendren F | title = P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain | journal = The EMBO Journal | volume = 29 | issue = 14 | pages = 2290–2300 | date = July 2010 | pmid = 20562826 | pmc = 2910276 | doi = 10.1038/emboj.2010.126 }}</ref><ref>{{cite journal | vauthors = Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K | title = P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury | journal = Nature | volume = 424 | issue = 6950 | pages = 778–783 | date = August 2003 | pmid = 12917686 | doi = 10.1038/nature01786 | s2cid = 4358793 }}</ref><ref>{{cite journal | vauthors = Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K | title = Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model | journal = Neuroscience Letters | volume = 504 | issue = 1 | pages = 57–61 | date = October 2011 | pmid = 21924325 | doi = 10.1016/j.neulet.2011.08.058 | s2cid = 32284927 }}</ref><ref>{{cite journal | vauthors = Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN | title = Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain | journal = Pain | volume = 114 | issue = 3 | pages = 386–396 | date = April 2005 | pmid = 15777864 | doi = 10.1016/j.pain.2005.01.002 | s2cid = 21486673 }}</ref>

== Effects on cytotoxic edema == Purinergic receptors have been suggested to play a role in the treatment of cytotoxic edema and brain infarctions. It was found that with treatment of the purinergic ligand 2-methylthioladenosine 5' diphosphate (2-MeSADP), which is an agonist and has a high preference for the purinergic receptor type 1 isoform (P2Y1R), significantly contributes to the reduction of an ischemic lesions caused by cytotoxic edema. Further pharmacological evidence has suggested that 2MeSADP protection is controlled by enhanced astrocyte mitochondrial metabolism through increased inositol triphosphate-dependent calcium release. There is evidence suggesting a relationship between the levels of ATP and cytotoxic edema, where low ATP levels are associated with an increased prevalence of cytotoxic edema. It is believed that mitochondria play an essential role in the metabolism of astrocyte energy within the penumbra of ischemic lesions. By enhancing the source of ATP provided by mitochondria, there could be a similar 'protective' effect for brain injuries in general.<ref>{{cite journal | vauthors = Zheng W, Watts LT, Holstein DM, Prajapati SI, Keller C, Grass EH, Walter CA, Lechleiter JD | title = Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria | journal = PLOS ONE | volume = 5 | issue = 12 | article-number = e14401 | date = December 2010 | pmid = 21203502 | pmc = 3008710 | doi = 10.1371/journal.pone.0014401 | doi-access = free | bibcode = 2010PLoSO...514401Z }}</ref>

== Effects on diabetes == Purinergic receptors have been implicated in the vascular complications associated with diabetes due to the effect of high-glucose concentration on ATP-mediated responses in human fibroblasts.<ref>{{cite journal | vauthors = Solini A, Chiozzi P, Falzoni S, Morelli A, Fellin R, Di Virgilio F | title = High glucose modulates P2X7 receptor-mediated function in human primary fibroblasts | journal = Diabetologia | volume = 43 | issue = 10 | pages = 1248–1256 | date = October 2000 | pmid = 11079743 | doi = 10.1007/s001250051520 | doi-access = free }}</ref>

== See also == * Purinergic signaling

== References == {{reflist|33em}}

== External links == * [http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1273 IUPHAR GPCR Database – Adenosine receptors] * [http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1294 IUPHAR GPCR Database – P2Y receptors] * {{MeshName|Purinergic+Receptors}}

Category:G protein-coupled receptors