Uracil nucleotide/cysteinyl leukotriene receptor is a G protein-coupled receptor that in humans is encoded by the GPR17 gene 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 an Orphan 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 for LTC4, LTD4, and uracil nucleotides. [7] In consequence, GPR17 attracted attention as a potential mediator of reactions caused by LTC4 and LTD4 viz., asthma, rhinitis, and urticarial triggered by allergens, nonsteroidal anti-inflammatory drugs, and exercise (see Aspirin-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-bearing oligodendrocytes do indeed respond to them. [7] In 2013 and 2014 reports, the International 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 and cysteinyl leukotriene receptor 2) and the purine P2Y subfamily of 12 receptors (see P2Y receptors), sharing 28 to 48% amino acid identity with them. GPR17 is a G protein coupled receptor that acts primarily through G proteins linked to the Gi alpha subunit but also to Gq alpha subunit. [7] [11] Matching these structural relationships, GPR17 has been reported to be activated by cysteinyl leukotrienes (i.e. LTC4 and LTD4) 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 and atherosclerosis-promoting oxysterols 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, and Cangrelor, which inhibits P2Y purinergic receptors and is approved in the USA as an antiplatelet 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 the central nervous system (CNS); it is overexpress in CNS tissues experiencing demyelination injuries; within 48 hours of the latter types of injuries, GPR17 expression is induced in dying neurons within and on the borders of injury, in infiltrating microglia and macrophages, and in activated oligodendrocyte precursor cells. [7]
Studies focusing on allergic and hypersensitivity reactions have found that the LTC4 and LTD4 ligands for Cysteinyl leukotriene receptor 1 (CysLTR1) and Cysteinyl 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 to IgE-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 mature oligodendrocytes 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 by uridine, Uridine diphosphate (UDP) and UDP-glucose to stimulate outward K+ channels and the aforementioned maturation responses in oligodendrocyte precursor cells; c) also activated by LTC4 and LTD4; d) more highly expressed in central nervous system (CNS) tissues of animal models undergoing ischemia, Experimental autoimmune encephalomyelitis, and focal demyelination as well as in the CNS tissues of humans suffering brain damage due to ischemia, trauma, and multiple 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; and g) acts to reduce inflammation, elevate hippocampus 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]
The GPR17 gene has also been found to regulate food intake response mediated by FOXO1. [16]
GPR17 has been proposed as a potential pharmacological target for the treatment of multiple sclerosis and traumatic brain injury in humans. [7] [15] [17]
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system, which is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory.
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Eicosanoids may also act as endocrine agents to control the function of distant cells.
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.
The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.
The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.
P2Y receptors are a family of purinergic G protein-coupled receptors, stimulated by nucleotides such as adenosine triphosphate, adenosine diphosphate, uridine triphosphate, uridine diphosphate and UDP-glucose. To date, 8 P2Y receptors have been cloned in humans: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14.
An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor or leukotriene receptor antagonist and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the immune system and serve to promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD. Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.
Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.
The urotensin-2 receptor (UR-II-R) also known as GPR14 is a class A rhodopsin family G protein coupled-receptor (GPCR) that is 386 amino acids long which binds primarily to the neuropeptide urotensin II.[1] The receptor quickly rose to prominence when it was found that when activated by urotensin II it induced the most potent vasoconstriction effect ever seen. While the precise function of the urotensin II receptor is not fully known it has been linked to cardiovascular effects, stress, and REM sleep.
Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene. GPR65 is also referred to as TDAG8.
P2Y purinoceptor 14 is a protein that in humans is encoded by the P2RY14 gene.
Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT). CYSLTR1, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans as well as models of the reactions in other animals.
2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the OXGR1 gene. The Gene has recently been nominated as a receptor not only for 2-oxogluterate but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTE4. Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.
G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
G-protein coupled receptor 3 is a protein that in humans is encoded by the GPR3 gene. The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction.
Cysteinyl leukotriene receptor 2, also termed CYSLTR2, is a receptor for cysteinyl leukotrienes (LT). CYSLTR2, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans. However, the first discovered receptor for these CsLTs, cysteinyl leukotriene receptor 1 (CysLTR1), appears to play the major role in mediating these reactions.
Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a protein that in humans is encoded by the OXER1 gene located on human chromosome 2p21; it is the principal receptor for the 5-Hydroxyicosatetraenoic acid family of carboxy fatty acid metabolites derived from arachidonic acid. The receptor has also been termed hGPCR48, HGPCR48, and R527 but OXER1 is now its preferred designation. OXER1 is a G protein-coupled receptor (GPCR) that is structurally related to the hydroxy-carboxylic acid (HCA) family of G protein-coupled receptors whose three members are HCA1 (GPR81), HCA2, and HCA3 ; OXER1 has 30.3%, 30.7%, and 30.7% amino acid sequence identity with these GPCRs, respectively. It is also related to the recently defined receptor, GPR31, for the hydroxyl-carboxy fatty acid 12-HETE.
The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.
The leukotriene (LT) receptors are G protein-coupled receptors that bind and are activated by the leukotrienes. They include the following proteins:
