Uracil nucleotide/cysteinyl leukotriene receptor is aG protein-coupled receptor that in humans is encoded by theGPR17gene located on chromosome 2 at position q21.[5][6] The actual activating ligands for and some functions of this receptor are disputed.
Initially discovered in 1998 as anOrphan receptor, i.e. a receptor whose activating ligand(s) and function were unknown, GPR17 was "deorphanized" in a study that reported it to be a receptor forLTC4,LTD4, anduracil nucleotides.[7] In consequence, GPR17 attracted attention as a potential mediator of reactions caused by LTC4 and LTD4 viz.,asthma,rhinitis, andurticarial triggered byallergens,nonsteroidal anti-inflammatory drugs, and exercise (seeAspirin-induced asthma). Subsequent reports, however, have varied in results: studies focusing on the allergen and non-allergen reactions find that GPR17-bearing cells do not respond to LTC4, LTD4, and uracil nucleotides[8] while studies focusing on nerve tissue find that certain types of GPR17-bearingoligodendrocytes do indeed respond to them.[7] In 2013 and 2014 reports, theInternational Union of Basic and Clinical Pharmacology took no position on which of these are true ligands for GPR17.[9][10] GPR17 is a constitutively active receptor, i.e. a receptor that has baseline activity which is independent of, although potentially increased by, its ligands.[9]
GPR17 has a structure which is intermediate between the cysteinyl leukotriene receptor group (i.e.cysteinyl leukotriene receptor 1 andcysteinyl leukotriene receptor 2) and thepurine P2Y subfamily of 12 receptors (seeP2Y receptors), sharing 28 to 48% amino acid identity with them. GPR17 is aG protein coupled receptor that acts primarily through G proteins linked to theGi alpha subunit but also toGq alpha subunit.[7][11] Matching these structural relationships, GPR17 has been reported to be activated by cysteinyl leukotrienes (i.e.LTC4 andLTD4) as well as the purines (i.e.,uridine,Uridine diphosphate (UDP),UDP-glucose). Further relating these receptors, GPR17 may dimerize (i.e. associate with) certain of the cited cysteinyl leukotriene or purine receptors in mediating cell responses and this dimerization may explain some of the discrepancies reported for the ability of these ligands to activate GPR17 as expressed in different cell types (see below section of Function). GPR17 is also activated by the emergency-signaling andatherosclerosis-promotingoxysterols and by synthetic compounds with broadly different structures. Relevant to its activating ligands as well as its reported interaction with other G protein coupled receptors, GPR17 is a promiscuous receptor.[7]
Montelukast which inhibits cysteinyl leukotriene receptor 1 and is in clinical use for the chronic and preventative treatment of LTC4- and LTD4-promoted allergic and non-allergic diseases, andCangrelor, which inhibits P2Y purinergic receptors and is approved in the USA as anantiplatelet drug, inhibit the GPR17 receptor.[7]
GPR17 was first clone form and is highly expressed in certain precursors of oligodendrocytes in the nerve tissue of thecentral nervous system (CNS); it is overexpress in CNS tissues experiencingdemyelination injuries; within 48 hours of the latter types of injuries, GPR17 expression is induced in dyingneurons within and on the borders of injury, in infiltratingmicroglia andmacrophages, and in activated oligodendrocyte precursor cells.[7]
Studies focusing on allergic and hypersensitivity reactions have found that the LTC4 and LTD4 ligands forCysteinyl leukotriene receptor 1 (CysLTR1) andCysteinyl leukotriene receptor 2, which mediate these reactions, have disputed findings that LTC4 and LTD4 are ligands for GPR17. They have shown that cells co-expressing both CysLTR1 and GPR17 receptors exhibit a marked reduction in binding LTC4 and that mice lacking GPR17 are hyper-responsive toIgE-induced passive cutaneous anaphylaxis. They therefore have nominated GPR17 as functioning to inhibit CysLTR1 in these model systems and as such might serve to dampen the acute reactions involving the cited LTs.[12]
Studies focusing on nerve tissue indicate that GPR17 is:a) highly expressed in precursors to matureoligodendrocytes but not expressed in mature oligodendrocytes, suggesting that GPR17 must be down-regulated in order for precursor cells to proceed to terminal oligodendrocyte differentiation;b) activated byuridine,Uridine diphosphate (UDP) andUDP-glucose to stimulate outwardK+ channels and the aforementioned maturation responses in oligodendrocyte precursor cells;c) also activated by LTC4 and LTD4;d) more highly expressed incentral nervous system (CNS) tissues of animal models undergoingischemia,Experimental autoimmune encephalomyelitis, and focaldemyelination as well as in the CNS tissues of humans suffering brain damage due toischemia, trauma, andmultiple sclerosis;e) expressed in injured neurons and associated with the rapid death and clearance of these neurons in a model of mouse spinal cord crush injury;f) acts to reduce the extent of spinal cord injury in the latter model based on the increased extent of injury in GPR17-depleted mice; andg) acts to reduce inflammation, elevatehippocampus neurogenesis, and improve learning and memory in a rat model of age-related cognitive impairment based on the effects of the GPR17 antagonist, montelukast, as well as of GPR17 depletion. The studies suggest that GPR17 is a sensor of damage in the CNS and participates in the resolution of this damage by clearing and/or promoting the re-myelination of injured neurons caused by a variety of insults perhaps including old age.[7][13][14][15]
TheGPR17 gene has also been found to regulatefood intake response mediated byFOXO1.[16]
GPR17 has been proposed as a potential pharmacological target for the treatment ofmultiple sclerosis andtraumatic brain injury in humans.[7][15][17]
