NTSR1 Membrane Protein Introduction

Introduction of NTSR1

The neurotensin receptor family is composed of three subtypes, NTS1, NTS2, and NTS3. Neurotensin receptor type 1 (NTSR1) is a protein that in humans is encoded by the NTSR1 gene. It also belongs to the family of 7TM, G protein-coupled receptors, and is activated by the 13-amino-acid peptide neurotensin (NTS). It is a high-affinity neurotensin receptor with 7 transmembrane spanning regions and exhibits high expression in aggressive malignant solid tumors such as mesothelioma, non–small-cell lung, breast, and head and neck squamous carcinomas.

Function of NTSR1 Membrane Protein

NTSR1 exerts different functions in many biological processes, including adult locomotory behavior, temperature homeostasis, regulation of sensory perception of pain, positive regulation of the apoptotic process, neuropeptide signaling pathway, chemical synaptic transmission, etc. Amongst, the well-studied is to activate multiple signal transduction in cancers to promote cell survival, proliferation, migration, and invasiveness.

Neurotensin (NTS) is a short, 13-amino-acid peptide that acts both as a neurotransmitter and a hormone, and exerts central actions that include the modulation of dopamine neurotransmission, hypothermia, opioid-independent analgesia and the inhibition of food intake. NTSR1 can mediate the multiple functions of testing as many as NTS, such as low blood pressure, high blood sugar, low body temperature, antinociception, and regulation of intestinal motility and secretion. And the structure-activity studies of NT have revealed that the minimal bioactive fragment corresponds to the C-terminal hexapeptide of NT, NT (8-13). Besides, NTSR1 has been linked, through Gα_i/o, Gα_q, and Gα_s coupling, to a variety of intracellular signaling cascades including cyclic AMP (cAMP), inositol phosphate (IP), and arachidonic acid accumulation as well as the activation/inhibition of mitogen-activated protein kinases (ERK1/2 and JNK) and serine/threonine protein kinase Akt.

Fig.1 Structure of NTSR1 membrane protein. (PDB: 7UL2)

Application of NTSR1 Membrane Protein in Literature

1. Xiao H., et al. A Novel Positive Feedback Loop Between NTSR1 and Wnt/beta-Catenin Contributes to Tumor Growth of Glioblastoma. Cellular physiology and biochemistry. 2017, 43(5): 2133-42. PubMed ID: 29065410
   
   

   The author of this group aimed to uncover the potential connection between NTS/NTSR1 signaling and Wnt/β-Catenin pathway. They found that NTS/NTSR1 induced the activation of mitogen-activated protein kinase (MAPK) and the NF-κB pathway, which further promoted the expression of Wnt proteins, including Wnt1, Wnt3a, and Wnt5a.

2. Agopiantz M., et al. Expression of neurotensin receptor 1 in endometrial adenocarcinoma is correlated with histological grade and clinical outcome. Virchows Archiv. 2017, 471(4): 521-30. PubMed ID: 28836043
   
   

   This article evaluated the contribution of NTS to endometrial carcinogenesis. NTSR1 overexpression is a poor prognostic factor in endometrial cancer, highlighting the contribution of NTS in endometrial cancer progression and its uses as a prognostic marker, and as a potential therapeutic target.

3. Yin X., et al. Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma. Amino acids. 2017, 49(8): 1325-35. PubMed ID: 28536844
   
   

   This article not only evaluated the NTSR1 expression in pancreatic cancer patient samples but also explored the PET and fluorescence imaging of NTR1 expression in pancreatic cancer animal models. And their results indicated that NTSR1 is a promising target for pancreatic ductal adenocarcinoma imaging and therapy.

4. Besserer-Offroy E., et al. The signaling signature of the neurotensin type 1 receptor with endogenous ligands. European journal of pharmacology. 2017, 805: 1-13. PubMed ID: 28341345.
   
   

   This article investigated the ability of activated hNTSR1, which was stably expressed by CHO-K1 cells, to directly engage G proteins, activate second messenger cascades and recruit β-arrestins. And found the characterization of the hNTSR1-mediated cellular signaling network will be helpful to accelerate the validation of potential NTSR1 biased ligands with an improved therapeutic/adverse effect profile.

5. Luckmann M., et al. In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist. Molecular informatics. 2016, 35(1): 19-24. PubMed ID: 27491650.
   
   

   The author of this group investigated the binding mode of SR48692 and other small molecule compounds to NTSR1, they applied an Automated Ligand-guided Backbone Ensemble Receptor Optimization protocol (ALiBERO), taking receptor flexibility and ligand knowledge into account. And their models provide new insights into small molecule ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacological potential of NTSR1 in neurological disorders and cancer.

6. Kamimae S., et al. Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors. Oncotarget. 2015, 6(30): 29975-90. PubMed ID: 26334593
   
   

   This article suggests that methylation of NTSR1 is involved in the noninvasive and lateral growth of colorectal tumors, while low levels methylation may result in activation of NTSR1 and then lead to the malignant potential.

7. Ouyang Q., et al. Neurotensin promotes the progression of malignant glioma through NTSR1 and impacts the prognosis of glioma patients. Mol Cancer. 2015, 14: 21. PubMed ID: 25644759
   
   

   This article demonstrates that the activation of NTSR1 by NTS accelerates the proliferation and invasion of glioma, and high expression levels of NTSR1 and NTS will lead to a poor prognosis in glioma patients.

8. Hu H.R., et al. Function and mechanism of neurotensin (NTS) and its receptor 1 (NTSR1) in occurrence and development of tumors. Zhongguo Zhong Yao Za Zhi. 2015, 40(13): 2524-36. PubMed ID: 26697673
   
   

   This review summarizes the roles of NTSR1/NTS and its mechanisms and discusses the possibility of its application to drugs targeting and clinical diagnosis.

9. Li J., et al. The NTSR1 gene modulates the association between hippocampal structure and working memory performance. Neuroimage. 2013, 75: 79-86. PubMed ID: 23110888
   
   

   This article indicates that the association between WM performance and the hippocampal structure is regulated by variation in the NTSR1 gene, and suggests that genetic background information should be taken into account in further studies of brain-behavior associations.

10. Lee S., et al. Structural dynamics and thermostabilization of neurotensin receptor 1. J Phys Chem B. 2015, 119(15): 4917-28. PubMed ID: 25807267
    
    

    This article provides valuable insights into the functioning and stability of NTSR1 by analyzing the structural dynamics and thermostabilization, which will be useful in the future design of thermostable mutants of other peptide GPCRs.

NTSR1 Preparation Options

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Reference

1. Robertson, M. J.; et al. Structure determination of inactive-state GPCRs with a universal nanobody. Nature Structural & Molecular Biology. 2022, 29(12): 1188-1195.

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