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NOP receptor

Family: Opioid receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 370 20q13.33 OPRL1 opiate receptor-like 1 49
Mouse 7 367 2 H2-4 Oprl1 opioid receptor-like 1 56
Rat 7 367 3q43 Oprl1 opiate receptor-like 1 7,64
Previous and Unofficial Names
OP4
ORL1
LY322
N/OFQ receptor
NOCIR
OOR
KOR-3
LC132 receptor-like
orphanin FQ receptor
kappa3-related opioid receptor
KOR3
LC132
MOR-C
OFQR
Oprl
XOR1
ROR-C
kappa-type 3 opioid receptor
nociceptin receptor
nociceptin receptor ORL1
opiate receptor-like 1
opioid receptor-like
opioid receptor-like 1
orphanin FQ receptor-a
orphanin FQ receptor-b
orphanin FQ receptor-e
peptide receptor
seven transmembrane G protein-coupled receptor
nociceptin/ orphaninFQ receptor
morc
NOP-r
Database Links
ChEMBL Target 138 (Hs), 10530 (Mm), 12965 (Rn)
DrugBank Target 4137 (Hs)
Ensembl ENSG00000125510 (Hs), ENSMUSG00000027584 (Mm), ENSRNOG00000016768 (Rn)
Entrez Gene 4987 (Hs), 18389 (Mm), 29256 (Rn)
GeneCards OPRL1 (Hs)
GenitoUrinary Development Molecular Anatomy Project Oprl1 (Mm)
HomoloGene 22609 (Hs)
Human Protein Reference Database 03971 (Hs)
InterPro P41146 (Hs), P35377 (Mm), P35370 (Rn)
KEGG Gene hsa:4987 (Hs), mmu:18389 (Mm), rno:29256 (Rn)
OMIM 602548 (Hs)
PhosphoSitePlus P41146 (Hs), P35377 (Mm), P35370 (Rn)
Protein Ontology (PRO) PRO:000001631 (Hs)
RefSeq Nucleotide NM_000913 (Hs), NM_011012 (Mm), NM_031569 (Rn)
RefSeq Protein NP_000904 (Hs), NP_035142 (Mm), NP_113757 (Rn)
TreeFam ENSG00000125510 (Hs), ENSMUSG00000027584 (Mm), ENSRNOG00000016768 (Rn)
UniGene Hs. 2859 (Hs)
UniProt P41146 (Hs), P35377 (Mm), P35370 (Rn)
Wikipedia NOP receptor
Opioid receptors
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the N/OFQ Opioid Receptor in Complex with a Peptide Mimetic
PDB Id:  4EA3
Resolution:  3.01Å
Species:  Human
References: 
Search for other structures on the PDB
Search by keyword: Opioid receptors NOP receptor Search by accession number: P35370, P41146, P35377
Natural/Endogenous Ligand(s)
nociceptin/orphanin FQ {Sp: Human, Mouse, Rat}
Rank order of potency (Human)
N/OFQ >> dynorphin A
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
UFP-102 Hs Full agonist 10.7 pKd 13
[3H]N/OFQ Hs Full agonist 10.2 pKd 20,48
[3H]Tyr14-N/OFQ Mm Full agonist 10.0 pKd 1
[(pF)Phe4]N/OFQ-(1-13)-NH2 Hs Full agonist 10.8 pKi 6
N/OFQ-NH2 Hs Full agonist 10.4 pKi 42
N/OFQ-(1-13)-NH2 Hs Full agonist 10.1 – 10.4 pKi 6,25,42,54
Ac-RYYRWK-NH2 Hs Partial agonist 10.0 pKi 42
nociceptin/orphanin FQ {Sp: Human, Mouse, Rat} Hs Full agonist 9.7 – 10.2 pKi 6,42,48,54
Ro64-6198 Hs Full agonist 9.6 pKi 33
[Arg14Lys15]N/OFQ Hs Full agonist 9.5 pKi 53
nociceptin/orphanin FQ {Sp: Human, Mouse, Rat} Mm Full agonist 9.4 pKi 19
Ac-RYYRWK-NH2 Mm Partial agonist 9.2 pKi 19
[F/G]N/OFQ-(1-13)-NH2 Hs Partial agonist 9.2 pKi 42
Ac-RYYRIK-NH2 Hs Partial agonist 9.1 pKi 42
Ac-RYYRIK-NH2 Mm Partial agonist 8.8 pKi 19
UFP-112 Hs Full agonist 8.39 – 9.71 pEC50 12,58
Ro64-6198 Hs Agonist 7.45 – 8.51 pEC50 12
View species-specific agonist tables
Agonist Comments
The above affinities are based on the use of radiolabelled N/OFQ to bind to membrane preparations from CHO cells containing the NOP receptor, and contain a rough average from, in some cases, multiple studies. This represents a high affinity binding conformation in the absence of Na+ and GTP, and low affinity values are not available. The Ki in intact cells, or in the presence of Na+ and GTP analogues can be different and multiple affinity sites have been observed.

Discrimination of full or partial agonism is very dependent on the level of receptor expression and on the assay used to monitor agonist effects. Many agents may behave as full agonists or potent partial agonists in cell lines expressing cloned receptors in high concentration, but in other environments they may show only weak agonist activity. The identification of agonist activity in the table is largely based on the ability to stimulate GTPγS binding in cell lines expressing cloned human NOP receptors. Agents giving 85% or greater stimulation than that given by N/OFQ have been characterized as Full Agonists [19,42]. Results may be different in brain membranes. In vivo and smooth muscle bioassay results may also be different and depend upon the assay performed.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
UFP-101 Hs Antagonist 10.2 pKi 11
SB 612111 Hs Antagonist 9.5 pKi 65
J-113397 Hs Antagonist 8.7 pKi 55
[Nphe1]N/OFQ-(1-13)-NH2 Hs Antagonist 8.4 pKi 11
JTC-801 Hs Antagonist 8.1 pKi 60
peptide III-BTD Hs Antagonist 7.6 pKi 2
J-113397 Hs Antagonist 8.3 pIC50 36
Antagonist Comments
The above affinities ase based on binding to receptors in membrane preparations and represent a rough average from, in some cases, multiple studies.
So far, no inverse agonists have been reported for the NOP receptor.
More details about the pharmacological profile of the NOP receptors and the chemistry of NOP ligands can be found in review articles [8-9,46,66].
Allosteric Regulator Comments
Although no small molecules are considered direct allosteric regulators of the NOP receptor, a number of proteins such as G protein-coupled receptor kinases, β-arrestins and G proteins clearly regulate receptor functions. Furthermore, sodium and guanyl nucleotides can modify the functional NOP complex and G protein interaction. Finally, other G protein-coupled receptors (i.e. the μ opioid receptor [63]) appear to be able to form heterodimers with NOP receptors, potentailly modifying the receptor activity.

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Potassium channel
Calcium channel
Other - See Comments
Comments:  NOP receptors have been shown to activate MAP kinase and phospholipase C/[Ca2+] [26].
References:  17,19,45,57,62
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
References: 
Tissue Distribution
Brain: cerebral > hippocampus, cerebellum, striatum.
Species:  Human
Technique:  Radioligand binding and in situ hybridisation.
References:  3
CNS: cortex, olfactory bulb, suprachiasmatic nucleus, amygdala, nucleus accumbens, thalamic nuclei, hypothalamus, hippocampus, septum, superior colliculus.
Species:  Mouse
Technique:  Radioligand binding.
References:  14-16,61
Brain: outer and medial cortical layers, subiculum, hippocampus, nucleus accumbens > inner cortical layer, pontine nuclei, thalamus, hypothalamus > cerebellum, striatum.
Species:  Rat
Technique:  Rad
References:  23
NOP receptors are located both pre- and post-synaptically in various areas of the CNS.
Brain: cingulate, retrosplenial, perirhinal, insular and occipital cortex, anterior and posteromedial cortical amygdaloid nuclei, basolateral amygdaloid nucleus, amygdaloid complex, posterior hippocampus, dorsal endopiriform, central medial thalamic, paraventricular, rhomboid thalamic, suprachiasmatic, ventromedial hypothalamic nuclei, mammillary complex, superficial gray layer of the superior colliculus, locus coeruleus, dorsal raphe nucleus > prefrontal, fronto–parietal, temporal, piriform cortex, dentate gyrus, anterior olfactory nucleus, olfactory tubercle, shell of nucleus accumbens, claustrum, lateral septum, laterodorsal thalamic, medial habenular, subthalamic, reuniens thalamic nuclei, subiculum, periaqueductal grey matter and pons > anterior and medial hippocampus, olfactory bulb, caudate putamen, the core of the nucleus accumbens, medial septum, ventrolateral, ventroposterolateral and mediodorsal thalamic nuclei, lateral and medial geniculate nuclei, hypothalamic area, substantia nigra, ventral tegmentum area and interpedoncular nucleus.
Spinal cord: dorsal and ventral horn.
Species:  Rat
Technique:  Radioligand binding.
References:  22
Tissue Distribution Comments
Receptor Distribution
Like the μ opioid receptor, the NOP receptor shows very dense binding in many caudal and rostral regions, but with a notably distinct binding profile. The distinction of labelling in comparison to the classical opioid receptors is most evident in the caudate putamen, where NOP receptors are relatively low. In contrast, structures such as the suprachiasmatic nucleus have an abundant expression of NOP receptors.
Studies of the distribution of NOP receptors in humans have also been limited to autoradiography and in situ hybridisation analysis. NOP receptors in the CNS appear to have a similar distribution in rat and human. It should be noted that NOP receptors appear far sooner and in larger numbers in the developing brain than the other opioid receptors do, suggesting an important role in development 179-184.
For a review of the tissue distribution of this receptor see 177.
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of musculature contraction of sections of mouse vas deferens following stimulation of the intramural nerves.
Species:  Mouse
Tissue:  Vas deferens.
Response measured:  Inhibition of electrically-evoked contractions.
References:  4,10
Measurement of adrenergic neuromuscular transmission in the rat anococcygeus muscle.
This tissue is selectively sensitive to N/OFQ and does not respond to classical opioid ligands; thus it can be considered a monoreceptor preparation.
Species:  Rat
Tissue:  Anococcygeus muscle.
Response measured:  Inhibition adrenergic motor response to electrical-field stimulation.
References:  27
Measurement of cAMP levels in CHO cells transfected with the human NOR receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  45
Measurement of cAMP levels in CHO cells transfected with the rat NOP receptor.
Species:  Rat
Tissue:  CHO cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  19
Measurement of Ca2+ channel activity in SH-SY5Y neuroblastoma cells endogenously expressing the NOP receptor.
Species:  Human
Tissue:  SH-SY5Y neuroblastoma cells.
Response measured:  Inhibition of N-type calcium current.
References:  17
Measurement of cAMP levels in BE(2)-C human neuroblastoma cells endogenously expressing the human NOP receptor.
Species:  Human
Tissue:  BE(2)-C neuroblastoma cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  38
Measurement of [35S]GTPγS binding in CHO cells transfected with the mouse κ receptor.
Species:  Mouse
Tissue:  CHO cells.
Response measured:  [35S]GTPγS binding.
References:  19,62
Measurement of [35S]GTPγS binding in mouse brain preperations.
Species:  Mouse
Tissue:  Brain membranes.
Response measured:  [35S]GTPγS binding.
References:  62
Physiological Functions
Inhibition of dopamine release.
Species:  Rat
Tissue:  In vivo.
References:  50
Inhibition of glutamate release.
Species:  Rat
Tissue:  Cerebrocortical slices.
References:  51
Inhibition of electrically-evoked muscle contraction in the vas deferens.
Species:  Mouse
Tissue:  Vas deferens.
References:  4,10
Inhibition of electrically-evoked muscle contraction of the colon.
Species:  Mouse
Tissue:  Colon.
References:  43
Inhibition of electrically-evoked muscle contraction of the colon.
Species:  Rat
Tissue:  Colon.
References:  43
Inhibition of electrically-evoked muscle contraction in the vas deferens.
Species:  Rat
Tissue:  Vas deferens.
References:  5
Inhibition of acetylcholine release.
Species:  Rat
Tissue:  In vivo.
References:  31
NOP agonist-induced inhibition of opiate analgesia, and potentially hyperalgesia after ICV injection. Direct hyperalgesic activity is unclear and may be due to stress-induced analgesia from ICV injection. The NOP agonist showed dose-related opposite modulation of nociception after peripheral or intrathecal injection. NOP agonist-induced antinociception or potentaition of morphine antinociception after intrathecal injection has also been reported.
Species:  Mouse
Tissue:  In vivo.
References:  29-30,45,47
NOP agonist-induced anxiolytic activity after ICV or peripheral injection.
Species:  Rat
Tissue:  In vivo.
References:  33
NOP agonist-induced anxiolytic activity after ICV or peripheral injection.
Species:  Mouse
Tissue:  In vivo.
References:  32
NOP agonist-induced anxiogenic activity.
Species:  Rat
Tissue:  In vivo.
References:  21
NOP agonist-induced cardiovascular depression and water diuretic activity after either ICV or intravenous administration.
Species:  Rat
Tissue:  In vivo.
References:  34-35
Inhibition of noradrenaline release.
Species:  Mouse
Tissue:  Cortex slices.
References:  59
Inhibition of glutamate release.
Species:  Rat
Tissue:  Cerebrocortical slices.
References:  51
Inhibition of serotonin release.
Species:  Rat
Tissue:  Neocortex.
References:  41
Physiological Functions Comments
For a review on the functional architecture of the NOP receptor, including information on splice variants, see reference [44].
Physiological Consequences of Altering Gene Expression
Mice lacking the gene coding for the NOP receptor (NOP-/- mice) are viable, breed well and appear to age normally.
NOP receptor knockout mice exhibit insufficient recovery of hearing ability from the adaptation to sound exposure.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  52
NOP receptor knockout mice exhibit facilitation of long-term potentiation and learning abilities.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  37
NOP receptor knockout mice exhibit normal sensitivity to acute nociceptive stimulation but pronociceptive phenotype in some nociceptive tests.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  18,28
NOP receptor knockout mice exhibit an antidepressant phenotype in the forced swimming assay.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  24
NOP receptor knockout mice exhibit a better locomotor performance in the rotarod test and less sensitivity to haloperidol-induced motor depression.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  39-40
NOP receptor knockout mice exhibit attenuation of morphine tolerance and dependence.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  62
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0002735 abnormal chemical nociception PMID: 12814369  9155012 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0002063 abnormal learning/memory/conditioning PMID: 9707118 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae		 MGI:97440  MP:0002734 abnormal mechanical nociception PMID: 16519664 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0002799 abnormal passive avoidance behavior PMID: 9707118 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0001413 abnormal response to new environment PMID: 9707118 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0001463 abnormal spatial learning PMID: 9707118 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0001968 abnormal touch/ nociception PMID: 9155012 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0001982 decreased chemically-elicited antinociception PMID: 9660760 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0003998 decreased thermal nociceptive threshold PMID: 12814369 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0003008 enhanced long term potentiation PMID: 9707118 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0009757 impaired behavioral response to morphine PMID: 11027224 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0001906 increased dopamine level PMID: 15030410 
Oprl1tm1Hta Oprl1tm1Hta/Oprl1tm1Hta
involves: 129S4/SvJae * C57BL/6J		 MGI:97440  MP:0004597 increased susceptibility to noise-induced hearing loss PMID: 9155012 
Oprl1tm1Dgen Oprl1tm1Dgen/Oprl1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6		 MGI:97440  MP:0002169 no abnormal phenotype detected

REFERENCES

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To cite this database page, please use the following:

Anna Borsodi, Girolamo Caló, Charles Chavkin, MacDonald J. Christie, Olivier Civelli, Brian M. Cox, Lakshmi A. Devi, Christopher Evans, Graeme Henderson, Volker Höllt, Brigitte Kieffer, Ian Kitchen, Mary-Jeanne Kreek, Lee-Yuan Liu-Chen, Jean-Claude Meunier, Philip S. Portoghese, Toni S. Shippenberg, Eric J. Simon, Lawrence Toll, John R. Traynor, Hiroshi Ueda, Yung H. Wong.
Opioid receptors: NOP receptor. Last modified on 15/02/2013. Accessed on 19/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=320.


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