Neurotensin receptor

Neurotensin receptors are transmembrane receptors that bind the neurotransmitter neurotensin.^[1]^[2] Two of the receptors encoded by the NTSR1 and NTSR2 genes contain seven transmembrane helices and are G protein coupled. Numerous crystal structures have been reported for the neurotensin receptor 1 (NTS₁).^[3] The third receptor has a single transmembrane domain and is encoded by the SORT1 gene.

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Ligands

Agonists

Peptide

Beta-lactotensin (NTS₂)^[4]
JMV-449
Neurotensin
Neuromedin N (NTS₁ selective)
PD-149,163 (NTS₁ selective, reduced amide bond 8-13 fragment of neurotensin)

Non-peptide

NTS₁ full agonist SRI-9829 ^[3]
Partial agonists derived from SR-48692^[5]

Antagonists

Levocabastine (NTS₂ selective, also H₁ histamine antagonist)^[6]
SR-48692 (NTS₁ selective)^[7]
SR-142948 (unselective, CAS# 184162-64-9)

Biophysical Investigation

Unusually for GPCRs, NTS1 can be expressed in an active form in the bacteria E. coli.^[8] It can be purified and analysed in vitro and has been analysed by a number of biophysical techniques such as surface plasmon resonance,^[9] FRET^[10] and cryo-electron microscopy.^[11] Furthermore, high-resolution crystal structures of NTS₁ have been determined in complex with the peptide full agonist NT8-13, the non-peptide full agonist SRI-9829, the partial agonist RTI-3a, and the antagonists / inverse agonists SR-48692 and SR-142948, as well as in the ligand-free apo state ^[3]

References

^ Vincent JP, Mazella J, Kitabgi P (1999). "Neurotensin and neurotensin receptors". Trends Pharmacol. Sci. 20 (7): 302–309. doi:10.1016/S0165-6147(99)01357-7. PMID 10390649.
^ Pelaprat D (2006). "Interactions between neurotensin receptors and G proteins". Peptides. 27 (10): 2476–2487. doi:10.1016/j.peptides.2006.04.027. PMID 16919370. S2CID 21730838.
^ ^a ^b ^c Deluigi M, Klipp A, Klenk C, Merklinger L, Eberle SA, Morstein L, Heine P, Mittl PR, Ernst P, Kamenecka TM, He Y, Vacca S, Egloff P, Honegger A, Plückthun A (January 2021). "Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism". Science Advances. 7 (5): eabe5504. Bibcode:2021SciA....7.5504D. doi:10.1126/sciadv.abe5504. PMC 7840143. PMID 33571132.
^ Yamauchi R, Usui H, Yunden J, Takenaka Y, Tani F, Yoshikawa M (April 2003). "Characterization of beta-lactotensin, a bioactive peptide derived from bovine beta-lactoglobulin, as a neurotensin agonist". Bioscience, Biotechnology, and Biochemistry. 67 (4): 940–3. doi:10.1271/bbb.67.940. PMID 12784648. S2CID 83609327.
^ Thomas JB, Navarro H, Warner KR, Gilmour B (March 2009). "The identification of nonpeptide neurotensin receptor partial agonists from the potent antagonist SR48692 using a calcium mobilization assay". Bioorganic & Medicinal Chemistry Letters. 19 (5): 1438–1441. doi:10.1016/j.bmcl.2009.01.024. PMC 4418176. PMID 19195889.
^ Bredeloux P, Costentin J, Dubuc I (December 2006). "Interactions between NTS2 neurotensin and opioid receptors on two nociceptive responses assessed on the hot plate test in mice". Behavioural Brain Research. 175 (2): 399–407. doi:10.1016/j.bbr.2006.09.016. PMID 17074405. S2CID 24790151.
^ Ferraro L, Tomasini MC, Mazza R, Fuxe K, Fournier J, Tanganelli S, Antonelli T (August 2008). "Neurotensin receptors as modulators of glutamatergic transmission". Brain Research Reviews. 58 (2): 365–373. doi:10.1016/j.brainresrev.2007.11.001. PMID 18096238. S2CID 25434443.
^ Attrill H, Harding PJ, Smith E, Ross S, Watts A (2009). "Improved yield of a ligand-binding GPCR expressed in E. coli for structural studies". Protein Expr Purif. 64 (1): 32–38. doi:10.1016/j.pep.2008.10.001. PMID 18976711.
^ Harding PJ, Hadingham TC, McDonnell JM, Watts A (2006). "Direct analysis of a GPCR-agonist interaction by surface plasmon resonance". Eur Biophys J. 35 (8): 709–712. doi:10.1007/s00249-006-0070-x. PMID 16708210. S2CID 7844675.
^ Harding PJ, Attrill H, Boehringer J, Ross S, Wadhams GH, Smith E, Armitage JP, Watts A (2009). "Constitutive dimerization of the G-protein coupled receptor, neurotensin receptor 1, reconstituted into phospholipid bilayers". Biophys. J. 96 (3): 964–973. Bibcode:2009BpJ....96..964H. doi:10.1016/j.bpj.2008.09.054. PMC 2716571. PMID 19186134.
^ Selmi DN, Adamson RJ, Attrill H, Goddard AD, Gilbert RJ, Watts A, Turberfield AJ (2011). "DNA-templated protein arrays for single-molecule imaging". Nano Lett. 11 (2): 657–660. Bibcode:2011NanoL..11..657S. doi:10.1021/nl1037769. PMID 21218848.

External links

"Neurotensin Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-04-24.
Neurotensin+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3
Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)
Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)
Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine D1 D2 D3 D4 D5 GHB receptor Histamine H1 H2 H3 H4 Melatonin (1A 1B 1C) TAAR (1 2 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 1 2 FPRL1 OXE Prostaglandin DP (1 2), EP (1 2 3 4), FP Prostacyclin Thromboxane
Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Hydroxycarboxylic acids 1 2 3 Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide

B/W (1
2)
FF (1
2)
S
Y (1
2
4
5)
Neuromedin (B
U (1
2))
Neurotensin (1
2)

Other

Anaphylatoxin (C3a
C5a (1
2))
Angiotensin (1
2)
Apelin
Bombesin
- BRS3
- GRPR
- NMBR)
- Bradykinin (B1
- B2)
Chemokine
Cholecystokinin (A
B)
Endothelin
- A
- B
Formyl peptide (1
2
3)
FSH
Galanin (1
2
3)
Gonadotropin-releasing hormone (1
2)
Ghrelin
Kisspeptin
Luteinizing hormone/choriogonadotropin
MAS (1
1L
D
E
F
G
X1
X2
X3
X4)
Melanocortin (1
2
3
4
5)
MCHR (1
2)
Motilin
Opioid (Delta
Kappa
Mu
Nociceptin & Zeta, but not Sigma)
Orexin (1
2)
Oxytocin
Prokineticin (1
2)
Prolactin-releasing peptide
Relaxin (1
2
3
4)
Somatostatin (1
2
3
4
5)
Tachykinin (1
2
3)
Thyrotropin
Thyrotropin-releasing hormone
Urotensin-II
Vasopressin (1A
1B
2)

Miscellaneous

Taste, bitter	TAS2R 1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60 Vomeronasal receptor type 1
Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)
Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin-like

Adhesion	ADGRB Brain-specific angiogenesis inhibitor 1 2 3 ADGRC Cadherin 1 2 3 ADGRE EMR 1 2 3 CD97 ADGRG 1 2 3 4 5 6 7 ADGRL Latrophilin 1 2 3 ELTD1
Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)
Other	Calcitonin CALCRL Corticotropin-releasing hormone (1 2) Glucagon (GR GIPR GLP1R GLP2R) Growth-hormone-releasing hormone PACAPR1 GPR Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste, sweet	TAS1R 1 2 3 Vomeronasal receptor, type 2
Other	Calcium-sensing receptor GABA_B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F: Frizzled & Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)
Smoothened	Smoothened

Neuropeptide receptors

G protein-coupled receptor

Hormone receptors

Hypothalamic	CRH FSH LHRH TRH Somatostatin
Pituitary	Vasopressin 1A 1B 2 Oxytocin LHCG TSH
Other	Atrial natriuretic factor NPR3 Calcitonin Cholecystokinin A B VIP