Urotensin-II receptor

Last updated
UTS2R
Identifiers
Aliases UTS2R , GPR14, UR-2-R, UTR, UTR2, urotensin 2 receptor
External IDs OMIM: 600896 MGI: 2183450 HomoloGene: 10345 GeneCards: UTS2R
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_018949
NM_001381897

NM_145440

RefSeq (protein)

NP_061822
NP_001368826

NP_663415

Location (UCSC) Chr 17: 82.37 – 82.38 Mb Chr 11: 121.05 – 121.05 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] While the precise function of the urotensin II receptor is not fully known it has been linked to cardiovascular effects, stress, and REM sleep.

Contents

Ligands

There are two known endogenous agonists for the urotensin II receptor. One is urotensin II whose mRNA is found in a variety of tissues including the brain and also blood vessels. It is a potent vasoconstrictor and can increase REM cycles. The other is urotensin II-Related Peptide (URP) which is found in a variety of tissues as well although at less concentrations then urotensin II. The one exception is in human reproductive tissue where the levels of URP are much higher than urotensin II.

Cellular Pathway

Activation protein kinase C Activation protein kinase C.svg
Activation protein kinase C

Urotensin II Receptor interacts with the G Protein whose alpha subunit is Gαq11 which is mainly involved in activating Protein Kinase C (PKC). This then activates phospholipase C which increases the intercellular amount of calcium through the activation of IP3 which is an intracellular molecule that acts as secondary messenger. IP3 will then release calcium which then activates PKC.

When the urotensin II receptor is activated it also promotes beta arrestin translocation. Beta arrestin is important for ceasing the response of a receptor to a stimuli. Beta arrestin also brings with it other proteins that internalize the receptor which also helps in desensitizing the cell to the stimuli. [6]

Tissue distribution

Based on RT-PCR techniques the urotensin II receptor appears to be expressed throughout the entire brain. [7] On the other hand, when using in situ hybridization technique which is less sensitive but provides more information of the anatomical location urotensin II receptor mRNA was shown to be restricted to the brainstem cholinergic neurons of the laterodorsal tegmental (LDT) and the pedunculopontine tegmental nuclei (PPT) both of which are important for REM sleep. [8] These two different results are because urotensin II receptor can also be found in blood vessels which is what the sensitive RT-PCR technique was likely detecting. Urotensin II receptors are also found in the cholinergic neurons of the spinal cord indicating some type of motor function.

Urotensin II receptors have also been found in other peripheral tissues and blood vessels. This suggests some effects on the cardiovascular system.

Function

CNS

When the urotensin II receptor is activated through an intracerebroventricular (icv) injection of urotensin II it causes an increase of corticotropin releasing factor through the activation of the hypothalamic paraventricular neurons (PVN) which lead to increased plasma levels of adrenocorticotropic hormones. C-fos levels which go up whenever there is an increase in neural activity were detected in the brain 20 minutes after the urotensin II was injected. The stimulation of the PVN by the activation of urotensin II receptor means that it directly affects the hypothalamus pituitary axis (HPA) which is important in the regulation of many important body functions. [9] Rats also exhibit many stress related behaviors when injected with urotensin II such as pacing and fidgeting in familiar environments.

REM sleep is controlled by the cholinergic neurons in the PPT and LDT. Local injection of urotensin II into the PPT to leads to increased REM sleep episodes where the firing of the cholinergic neurons was observed through electrophysiological studies. The studies also showed there was no effect on the non-cholinergic neurons. Wakefulness and slow wave sleep were not affected by the activation of the urotensin II receptor. [10]

Cardiovascular

Short term effects of the activation of the urotensin II receptor is the burst intercellular calcium in the aorta which causes vasoconstriction of the vessel. There is also evidence that there are long term effects of the activation of the urotensin II receptor which could play a role in cardiomyocytic hypertrophy. [11]

Gene

Human urotensin II receptor is located on chromosome 17q25 as an intronless gene. There are no known subtypes of the receptor but the possibility cannot be discounted. It has similar domain sequences to the somatostatin receptor, and in lab conditions can be activated by somatostatin. [12]

Clinical significance

Mutations

There is one single-nucleotide polymorphism that is known to occur in humans regarding the urotensin II receptor. R1483.50 is instead H1483.50 which effects how the cell responds when the urotensin II receptor is activated. The receptor cannot activate the PKC but it can still activate the ERK1/2 pathway although it is a little bit slower.

There have been studies done on specific amino acids on the urotensin II receptor especially the ones that are homologous to the other members of the rhodopsin family. These include, D972.50, E1473.49, and Y1493.50. In all cases the amino acids were converted to alanine and their effects were observed. The mutated D972.50 receptor could not activate PKC nor could it activate the ERK1/2 pathway. This meant that it affected the activation of both pathways and plays a critical role. The other two amino acids which were mutated E1473.49 and Y1493.50 still activated both PKC and ERK1/2 suggesting that they did not play a critical role in the activation of the pathway. [13]

Related Research Articles

G protein-coupled receptor Class of cell surface receptors coupled to G-Protein associated intracelular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.

Muscarinic acetylcholine receptor Acetylcholine receptors named for their selective binding of muscarine

Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.

Endothelin

Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

Kisspeptin

Kisspeptins are proteins encoded by the KISS1 gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.

Glucagon-like peptide-1 receptor Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a receptor protein found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of G protein-coupled receptors. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

δ-opioid receptor Opioid receptor

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

Urotensin-II Chemical compound

Urotensin-II (U-II) is a peptide ligand that is the strongest known vasoconstrictor. Because of the involvement of the UII system in multiple biological systems such as the cardiovascular, nervous, endocrine, and renal, it represents a promising target for the development of new drugs.

KiSS1-derived peptide receptor Mammalian protein found in Homo sapiens

The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.

Muscarinic acetylcholine receptor M<sub>3</sub> Protein-coding gene in the species Homo sapiens

The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.

GPR35 G protein-coupled receptor

G protein-coupled receptor 35 also known as GPR35 is a G protein-coupled receptor which in humans is encoded by the GPR35 gene. Heightened expression of GPR35 is found in immune and gastrointestinal tissues, including the crypts of Lieberkühn.

GPR17 Protein-coding gene in the species Homo sapiens

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. The actual activating ligands for and some functions of this receptor are disputed.

Hydroxycarboxylic acid receptor 3 Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 3 (HCA3), also known as niacin receptor 2 (NIACR2) and GPR109B, is a protein which in humans is encoded by the HCAR3 gene. HCA3, like the other hydroxycarboxylic acid receptors HCA1 and HCA2, is a Gi/o-coupled G protein-coupled receptor (GPCR). The primary endogenous agonists of HCA3 are 3-hydroxyoctanoic acid and kynurenic acid. HCA3 is also a low-affinity biomolecular target for niacin (aka nicotinic acid).

Prostaglandin DP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.

GPR119 Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.

Hydroxycarboxylic acid receptor 2 Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 2 (HCA2), also known as niacin receptor 1 (NIACR1) and GPR109A, is a protein which in humans is encoded by the HCAR2 gene. HCA2, like the other hydroxycarboxylic acid receptors HCA1 and HCA3, is a Gi/o-coupled G protein-coupled receptor (GPCR). The primary endogenous agonists of HCA2 are D-β-hydroxybutyric acid and butyric acid (and their conjugate bases, β-hydroxybutyrate and butyrate). HCA2 is also a high-affinity biomolecular target for niacin (aka nicotinic acid).

GPR3

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.

GRK5

G protein-coupled receptor kinase 5 is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

Formyl peptide receptor 1 Protein-coding gene in the species Homo sapiens

Formyl peptide receptor 1 is a cell surface receptor protein that in humans is encoded by the formyl peptide receptor 1 (FPR1) gene. This gene encodes a G protein-coupled receptor cell surface protein that binds and is activated by N-Formylmethionine-containing oligopeptides, particularly N-Formylmethionine-leucyl-phenylalanine (FMLP). FPR1 is prominently expressed by mammalian phagocytic and blood leukocyte cells where it functions to mediate these cells' responses to the N-formylmethionine-containing oligopeptides which are released by invading microorganisms and injured tissues. FPR1 directs these cells to sites of invading pathogens or disrupted tissues and then stimulates these cells to kill the pathogens or to remove tissue debris; as such, it is an important component of the innate immune system that operates in host defense and damage control.

Urotensin II–related peptide

Urotensin II-related peptide (URP) is a cyclic neuropeptide that is found in all vertebrates that have been genome sequenced so far. It has a long lasting hypotensive effect and may also regulate reproduction. It is part of the Urotensin II system and is one of the two endogenous ligands for rats, mice, and possibly humans.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039321 - Ensembl, May 2017
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  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. Gartlon J, Parker F, Harrison DC, Douglas SA, Ashmeade TE, Riley GJ, Hughes ZA, Taylor SG, Munton RP, Hagan JJ, Hunter JA, Jones DN (2001). "Central effects of urotensin-II following ICV administration in rats". Psychopharmacology. 155 (4): 426–33. doi:10.1007/s002130100715. PMID   11441433. S2CID   22774771.
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  9. Watson AM, Lambert GW, Smith KJ, May CN (2003). "Urotensin II acts centrally to increase epinephrine and ACTH release and cause potent inotropic and chronotropic actions". Hypertension. 42 (3): 373–9. doi: 10.1161/01.HYP.0000084633.85427.E6 . PMID   12885791.
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  11. Saetrum Opgaard O, Nothacker H, Ehlert FJ, Krause DN (2000). "Human urotensin II mediates vasoconstriction via an increase in inositol phosphates". European Journal of Pharmacology. 406 (2): 265–71. doi:10.1016/s0014-2999(00)00672-5. PMID   11020490.
  12. Nothacker HP, Wang Z, McNeill AM, Saito Y, Merten S, O'Dowd B, Duckles SP, Civelli O (1999). "Identification of the natural ligand of an orphan G-protein-coupled receptor involved in the regulation of vasoconstriction". Nature Cell Biology. 1 (6): 383–5. doi:10.1038/14081. PMID   10559967. S2CID   41304445.
  13. Proulx CD, Holleran BJ, Boucard AA, Escher E, Guillemette G, Leduc R (2008). "Mutational analysis of the conserved Asp2.50 and ERY motif reveals signaling bias of the urotensin II receptor". Molecular Pharmacology. 74 (3): 552–61. doi:10.1124/mol.108.045054. PMID   18509066. S2CID   9019351.

Further reading