NTS<sub>2</sub> receptor | Neurotensin receptors | IUPHAR/BPS Guide to PHARMACOLOGY

Top ▲

NTS2 receptor

Target not currently curated in GtoImmuPdb

Target id: 310

Nomenclature: NTS2 receptor

Family: Neurotensin receptors

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 410 2p25.1 NTSR2 neurotensin receptor 2 30
Mouse 7 417 12 A1.1 Ntsr2 neurotensin receptor 2 18,29
Rat 7 416 6 Ntsr2 neurotensin receptor 2 7
Previous and Unofficial Names
levocabastine-sensitive neurotensin receptor | NTRL [4] | NTR2 | high-affinity levocabastine-sensitive neurotensin receptor | neurotensin receptor type 2 | NT2R
Database Links
Specialist databases
GPCRDB ntr2_human (Hs), ntr2_mouse (Mm), ntr2_rat (Rn)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Associated Proteins
Interacting Proteins
Name Effect References
NTS3/sortilin Functional complex between NTS2 and NTS3 is essential for the NT response in pancreatic β cells. 6
Natural/Endogenous Ligands
neuromedin N {Sp: Human} , neuromedin N {Sp: Mouse, Rat}
neurotensin {Sp: Human, Mouse, Rat, Bovine}
xenin {Sp: Human, Mouse, Rat}
Comments: Neurotensin is the most potent endogenous agonist
Potency order of endogenous ligands (Human)
neurotensin (NTS, P30990) = neuromedin N  [18]

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]neurotensin (human, mouse, rat) Mm Full agonist 8.6 pKd 3,18
pKd 8.6 [3,18]
JMV431 Hs Full agonist 7.0 pKd 22
pKd 7.0 [22]
neurotensin {Sp: Human, Mouse, Rat, Bovine} Hs Full agonist 8.8 pKi 22
pKi 8.8 [22]
JMV458 Hs Full agonist 8.7 pKi 22
pKi 8.7 [22]
JMV2004 Hs Full agonist 7.2 pKi 22
pKi 7.2 [22]
JMV457 Hs Full agonist 6.8 pKi 22
pKi 6.8 [22]
levocabastine Hs Full agonist 6.8 pKi 18,22
pKi 6.8 [18,22]
meclinertant Hs Full agonist 6.4 pKi 22
pKi 6.4 [22]
[125I]neurotensin (human, mouse, rat) Rn Full agonist 9.1 pIC50 7
pIC50 9.1 [7]
Trp11-neurotensin Mm Full agonist 8.8 – 9.0 pIC50 3
pIC50 8.8 – 9.0 [3]
xenin {Sp: Human, Mouse, Rat} Mm Full agonist 8.7 – 8.8 pIC50 3
pIC50 8.7 – 8.8 [3]
neuromedin N {Sp: Mouse, Rat} Mm Full agonist 8.6 – 8.8 pIC50 3
pIC50 8.6 – 8.8 [3]
neurotensin {Sp: Human, Mouse, Rat, Bovine} Mm Full agonist 8.5 – 8.7 pIC50 3
pIC50 8.5 – 8.7 [3]
levocabastine Mm Full agonist 8.4 – 8.7 pIC50 3
pIC50 8.4 – 8.7 [3]
neuromedin N {Sp: Mouse, Rat} Rn Full agonist 8.3 pIC50 7
pIC50 8.3 [7]
neurotensin {Sp: Human, Mouse, Rat, Bovine} Rn Full agonist 8.2 pIC50 9
pIC50 8.2 [9]
levocabastine Rn Partial agonist 8.0 pIC50 7
pIC50 8.0 [7]
[D-Trp11]neurotensin Mm Full agonist 7.5 – 7.6 pIC50 3
pIC50 7.5 – 7.6 [3]
meclinertant Mm Full agonist 7.1 pIC50 3
pIC50 7.1 [3]
Thr10contulakin-G Rn Full agonist 6.8 pIC50 9
pIC50 6.8 [9]
contulakin-G Rn Full agonist 6.1 pIC50 9
pIC50 6.1 [9]
View species-specific agonist tables
Agonist Comments
The sequence of neurotensin is identical for all mammalian species.

Xenopsin is a Xenopus laevis peptide similar to neurotensin [1].

Neuromedin N is expressed with neurotensin from the precursor [10].

Contulakin-G is an analogue of neurotensin from Conus geographus venum [9].

Levocabastine was originally developed as an antagonist of histamine receptor H1 [21].

JMV431 is a pseudo-peptide neurotensin analogue [12].
Antagonist Comments
SR48692, a NTS1 antagonist acts as an agonist both on human and mouse NTS2 receptors [4,30].
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Comments:  The injection of cRNAs corresponding to the mouse NTS2 receptor into Xenopus oocytes leads to a protein expressed at the oocyte surface that activates chloride currents upon neurotensin stimulation.
References:  4,18
Secondary Transduction Mechanisms
Comments:  Neurotensin activation of the rat NTS2 receptor induces Erk1/2 phosphorylation that is dependednt on receptor internalisation.
References:  14,26
Tissue Distribution
Brain: olfactory system, cerebral and cerebellar cortices, hippocampal formation and brainstem structures implicated in descending antinociceptive influences (periaqueductal gray, nucleux raphe magnus).
Species:  Mouse
Technique:  in situ hybridisation.
References:  24
Endocrine pancreas
Species:  Mouse
Technique:  Immunohistochemistry
References:  8
Brain: high densities of binding sites were observed in the cingulate, insular, temporal, occipital, enthorhinal cortex, amygdaloid complex, septohippocampal nuclei, medial thalamus, mammillary bodies and superior colliculi; a moderate labelling was observed in the anterior and medial hippocampus, olfactory tubercle, hypothalamus, periaqueductal gray matter, caudate putamen, nucleus accumbens, septum, lateral thalamus, dorsal raphe nucleus and cerebellum.
Species:  Rat
Technique:  Radioligand binding using [3H]levocabastine.
References:  2
Brain: astrocytes.
Species:  Rat
Technique:  in situ hybridisation.
References:  19
Dorsal root ganglia (DRG): strong labelling was observed in small and large ganglion cells. Quantitative analysis revealed that the NTS2 receptor was colocalised with the following neuronal markers: 42% with IB4, 37% with Substance P and 19% with CGRP.
Species:  Rat
Technique:  Immunofluorescence.
References:  25
Spinal cord: NTS2 immunoreactivity was detected within the superficial layers of the dorsal horn in the lumbar spinal cord. A dense plexus of NTS2 was observed in laminas I and II.
Species:  Rat
Technique:  immunocytochemistry.
References:  25
High densities of NTS2 immunoreactive nerve cell bodies and/or processes were detected in many regions documented to receive a dense neurotensinergic innervation, such as the olfactory bulb, bed nucleus of the stria terminalis, magnocellular preoptic nucleus, amygdaloid complex, anterodorsal thalamic nucleus, substantia nigra, ventral tegmental area and several brainstem nuclei. Also, structures implicated in the descending control of nociceptive inputs (e.g. the periaqueductal gray, dorsal raphe, gigantocellular reticular nucleus, pars alpha, lateral paragigantocellular and raphe magnus).
Species:  Rat
Technique:  immunocytochemistry.
References:  27
Species:  Rat
Technique:  Differential radioligand binding.
References:  15
Expression Datasets

Show »

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]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays
Measurement of chloride current in Xenopus oocytes transfected with the mouse NTS2 receptor.
Species:  Mouse
Tissue:  Xenopus oocytes.
Response measured:  Stimulation of chloride current by neurotensin and by the NTS1 receptor antagonist SR48692.
References:  4,18
Measurement of IP formation in CHO cells transfected with the human NTS2 receptor.
Species:  Human
Tissue:  CHO cells stably expressing recombinant NTS2 receptors.
Response measured:  Enhancement of IP formation by the NTS1 antagonist SR48692, effect antagonised by NT and levocabastine.
References:  30
Measurement of arachidonic acid release in CHO cells transfected with the human NTS2 receptor.
Species:  Human
Tissue:  CHO cells stably expressing recombinant NTS2 receptors.
Response measured:  Activation of arachidonic acid release by the NTS1 antagonist SR48692, effect antagonised by NT and levocabastine.
References:  30
Measurement of MAP kinases activity in CHO cells transfected with the human NTS2 receptor.
Species:  Human
Tissue:  CHO cells stably expressing recombinant NTS2 receptors.
Response measured:  Stimulation of MAP kinases by the NTS1 antagonist SR48692, effect antagonist by NT and levocabastine.
References:  30
Measurement of IP formation in COS cells transfected with the human NTS2 receptor.
Species:  Human
Tissue:  COS cells expressing recombinant human NTS2 receptors.
Response measured:  Constitutive IP formation, enhanced by the NTS1 antagonist SR48692 and reversed by NT and levocabastine.
References:  22
Measurement of MAP kinases Erk1/2 activity in primary cultured rat cerebellar granule cells expressing NTS2 but not NTS1.
Species:  Rat
Tissue:  Cerebellar granule cells expressing endogenous NTS2.
Response measured:  Activation of ERK1/2 phosphorylation by NT and levocabastine but not by SR48692.
References:  26
Measurement of MAP kinases Erk1/2 activity upon the dependence of internalisation in COS cells transfected with the rat NTS2 receptor.
Species:  Rat
Tissue:  COS cells expressing recombinant rat NTS2 receptors.
Response measured:  Internalisation-dependent activation of MAP kinases Erk1/2.
References:  14
Physiological Functions
Species:  Rat
Tissue:  In vivo
References:  11,16,23,28
Species:  Mouse
Tissue:  In vivo (brain).
References:  13
Species:  Rat
Tissue:  In vivo (spinal cord).
References:  25
Protection against apoptosis
Species:  Mouse
Tissue:  Endocrine pancreas
References:  6
Physiological Consequences of Altering Gene Expression
NTS2 knockout mice do not show any developmental deficits. However, these mice allowed to definitively demonstrate the role of NTS2 in the nociceptive properties of neurotensin.
Species:  Mouse
Technique:  Gene targeting in embryonic stem cells.
References:  17
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ntsr2tm1Dafe Ntsr2tm1Dafe/Ntsr2tm1Dafe
MGI:108018  MP:0001406 abnormal gait PMID: 20399236 
Ntsr2tm1Dafe Ntsr2tm1Dafe/Ntsr2tm1Dafe
MGI:108018  MP:0001489 decreased startle reflex PMID: 20399236 
Ntsr2tm1Dafe Ntsr2tm1Dafe/Ntsr2tm1Dafe
MGI:108018  MP:0009141 increased prepulse inhibition PMID: 20399236 
Ntsr2tm1Hmno Ntsr2tm1Hmno/Ntsr2tm1Hmno
involves: 129P2/OlaHsd * C57BL/6J
MGI:108018  MP:0001973 increased thermal nociceptive threshold PMID: 14725975 
Biologically Significant Variants
Type:  Splice variant
Species:  Mouse
Description:  A splice variant corresponding to a deletion of 181 bp has been identified the mouse brain. The expressed protein is truncated to 281 amino acids and bears only 5 transmembrane domains.
References:  5
Type:  Splice variant
Species:  Rat
Description:  A splice variant corresponding to a deletion of 181 bp has been identified in the rat brain. The expressed protein is truncated to 281 amino acids and bears only 5 transmembrane domains. The rat splice variant binds neurotensin with a very poor affinity (10μM).
References:  20


Show »

1. Araki K, Tachibana S, Uchiyama M, Nakajima T, Yasuhara T. (1975) Isolation and structure of a new active peptide xenopsin on rat stomach strip and some biogenic amines in the skin of Xenopus laevis. Chem Pharm Bull (Tokyo), 23: 3132-3140. [PMID:1218451]

2. Asselin ML, Dubuc I, Coquerel A, Costentin J. (2001) Localization of neurotensin NTS2 receptors in rat brain, using. Neuroreport, 12: 1087-1091. [PMID:11303751]

3. Botto JM, Chabry J, Sarret P, Vincent JP, Mazella J. (1998) Stable expression of the mouse levocabastine-sensitive neurotensin receptor in HEK 293 cell line: binding properties, photoaffinity labeling, and internalization mechanism. Biochem. Biophys. Res. Commun., 243 (2): 585-90. [PMID:9480852]

4. Botto JM, Guillemare E, Vincent JP, Mazella J. (1997) Effects of SR 48692 on neurotensin-induced calcium-activated chloride currents in the Xenopus oocyte expression system: agonist-like activity on the levocabastine-sensitive neurotensin receptor and absence of antagonist effect on the levocabastine insensitive neurotensin receptor. Neurosci. Lett., 223 (3): 193-6. [PMID:9080465]

5. Botto JM, Sarret P, Vincent JP, Mazella J. (1997) Identification and expression of a variant isoform of the levocabastine-sensitive neurotensin receptor in the mouse central nervous system. FEBS Lett., 400 (2): 211-4. [PMID:9001400]

6. Béraud-Dufour S, Coppola T, Massa F, Mazella J. (2009) Neurotensin receptor-2 and -3 are crucial for the anti-apoptotic effect of neurotensin on pancreatic beta-TC3 cells. Int. J. Biochem. Cell Biol., 41 (12): 2398-402. [PMID:19891061]

7. Chalon P, Vita N, Kaghad M, Guillemot M, Bonnin J, Delpech B, Le Fur G, Ferrara P, Caput D. (1996) Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett., 386 (2-3): 91-4. [PMID:8647296]

8. Coppola T, Béraud-Dufour S, Antoine A, Vincent JP, Mazella J. (2008) Neurotensin protects pancreatic beta cells from apoptosis. Int. J. Biochem. Cell Biol., 40 (10): 2296-302. [PMID:18456542]

9. Craig AG, Norberg T, Griffin D, Hoeger C, Akhtar M, Schmidt K, Low W, Dykert J, Richelson E, Navarro V et al.. (1999) Contulakin-G, an O-glycosylated invertebrate neurotensin. J. Biol. Chem., 274 (20): 13752-9. [PMID:10318778]

10. Dobner PR, Barber DL, Villa-Komaroff L, McKiernan C. (1987) Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor. Proc. Natl. Acad. Sci. U.S.A., 84 (10): 3516-20. [PMID:3472221]

11. Doré-Savard L, Roussy G, Dansereau MA, Collingwood MA, Lennox KA, Rose SD, Beaudet N, Behlke MA, Sarret P. (2008) Central delivery of Dicer-substrate siRNA: a direct application for pain research. Mol. Ther., 16 (7): 1331-9. [PMID:18523447]

12. Doulut S, Rodriguez M, Lugrin D, Vecchini F, Kitabgi P, Aumelas A, Martinez J. (1992) Reduced peptide bond pseudopeptide analogues of neurotensin. Pept. Res., 5 (1): 30-8. [PMID:1623301]

13. Dubuc I, Sarret P, Labbé-Jullié C, Botto JM, Honoré E, Bourdel E, Martinez J, Costentin J, Vincent JP, Kitabgi P et al.. (1999) Identification of the receptor subtype involved in the analgesic effect of neurotensin. J. Neurosci., 19 (1): 503-10. [PMID:9870978]

14. Gendron L, Perron A, Payet MD, Gallo-Payet N, Sarret P, Beaudet A. (2004) Low-affinity neurotensin receptor (NTS2) signaling: internalization-dependent activation of extracellular signal-regulated kinases 1/2. Mol. Pharmacol., 66 (6): 1421-30. [PMID:15361549]

15. Kitabgi P, Rostène W, Dussaillant M, Schotte A, Laduron PM, Vincent JP. (1987) Two populations of neurotensin binding sites in murine brain: discrimination by the antihistamine levocabastine reveals markedly different radioautographic distribution. Eur. J. Pharmacol., 140 (3): 285-93. [PMID:2888670]

16. Lafrance M, Roussy G, Belleville K, Maeno H, Beaudet N, Wada K, Sarret P. (2010) Involvement of NTS2 receptors in stress-induced analgesia. Neuroscience, 166 (2): 639-52. [PMID:20035838]

17. Maeno H, Yamada K, Santo-Yamada Y, Aoki K, Sun YJ, Sato E, Fukushima T, Ogura H, Araki T, Kamichi S et al.. (2004) Comparison of mice deficient in the high- or low-affinity neurotensin receptors, Ntsr1 or Ntsr2, reveals a novel function for Ntsr2 in thermal nociception. Brain Res., 998 (1): 122-9. [PMID:14725975]

18. Mazella J, Botto JM, Guillemare E, Coppola T, Sarret P, Vincent JP. (1996) Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain. J. Neurosci., 16 (18): 5613-20. [PMID:8795617]

19. Nouel D, Sarret P, Vincent JP, Mazella J, Beaudet A. (1999) Pharmacological, molecular and functional characterization of glial neurotensin receptors. Neuroscience, 94 (4): 1189-97. [PMID:10625058]

20. Perron A, Sarret P, Gendron L, Stroh T, Beaudet A. (2005) Identification and functional characterization of a 5-transmembrane domain variant isoform of the NTS2 neurotensin receptor in rat central nervous system. J. Biol. Chem., 280 (11): 10219-27. [PMID:15637074]

21. Pipkorn U, Bende M, Hedner J, Hedner T. (1985) A double-blind evaluation of topical levocabastine, a new specific H1 antagonist in patients with allergic conjunctivitis. Allergy, 40 (7): 491-6. [PMID:2866725]

22. Richard F, Barroso S, Martinez J, Labbé-Jullié C, Kitabgi P. (2001) Agonism, inverse agonism, and neutral antagonism at the constitutively active human neurotensin receptor 2. Mol. Pharmacol., 60 (6): 1392-8. [PMID:11723247]

23. Roussy G, Dansereau MA, Baudisson S, Ezzoubaa F, Belleville K, Beaudet N, Martinez J, Richelson E, Sarret P. (2009) Evidence for a role of NTS2 receptors in the modulation of tonic pain sensitivity. Mol Pain, 5: 38. [PMID:19580660]

24. Sarret P, Beaudet A, Vincent JP, Mazella J. (1998) Regional and cellular distribution of low affinity neurotensin receptor mRNA in adult and developing mouse brain. J Comp Neurol, 394: 344-356. [PMID:9579398]

25. Sarret P, Esdaile MJ, Perron A, Martinez J, Stroh T, Beaudet A. (2005) Potent spinal analgesia elicited through stimulation of NTS2 neurotensin receptors. J. Neurosci., 25 (36): 8188-96. [PMID:16148226]

26. Sarret P, Gendron L, Kilian P, Nguyen HM, Gallo-Payet N, Payet MD, Beaudet A. (2002) Pharmacology and functional properties of NTS2 neurotensin receptors in cerebellar granule cells. J. Biol. Chem., 277 (39): 36233-43. [PMID:12084713]

27. Sarret P, Perron A, Stroh T, Beaudet A. (2003) Immunohistochemical distribution of NTS2 neurotensin receptors in the rat central nervous system. J. Comp. Neurol., 461 (4): 520-38. [PMID:12746866]

28. Smith KE, Boules M, Williams K, Fauq AH, Richelson E. (2011) The role of NTS2 in the development of tolerance to NT69L in mouse models for hypothermia and thermal analgesia. Behav. Brain Res., 224 (2): 344-9. [PMID:21718721]

29. Sun YJ, Maeno H, Aoki S, Wada K. (2001) Mouse neurotensin receptor 2 gene (Ntsr2): genomic organization, transcriptional regulation and genetic mapping on chromosome 12. Brain Res. Mol. Brain Res., 95 (1-2): 167-71. [PMID:11687289]

30. Vita N, Oury-Donat F, Chalon P, Guillemot M, Kaghad M, Bachy A, Thurneyssen O, Garcia S, Poinot-Chazel C, Casellas P et al.. (1998) Neurotensin is an antagonist of the human neurotensin NT2 receptor expressed in Chinese hamster ovary cells. Eur. J. Pharmacol., 360 (2-3): 265-72. [PMID:9851594]


Show »

How to cite this page

Select citation format: