Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Neurotensin Receptor (NTSR)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_196

Synonyms

 NTR;  NTS

Historical Background

Neurotensin was originally isolated from bovine hypothalamus by Carraway and Leeman in 1973 and was identified as a 13 amino acid peptide (Carraway and Leeman 1973). It was named “neurotensin” in view of its hypotensive activity. Neurotensin is produced by neurons in the central nervous system (CNS) and N cells of the gastrointestinal tract. Neurotensin acts as a hormone and a neurotransmitter or neuromodulator in the periphery and in the CNS, respectively. Neurotensin is involved in the regulation of a number of physiological functions such as analgesia, neurodevelopment, neurodegeneration, thermal regulation, metabolic regulation, pituitary hormone secretion, gastrointestinal motility, and inflammation. It was later discovered that neurotensin is also present in several types of tumors and is implicated in tumorigenesis and tumor progression. Thus, signaling pathways downstream of neurotensin could be a potential drug target for the treatment of a variety of diseases. However, we had to wait 17 years to see the first receptor for neurotensin (neurotensin receptor 1 (NTSR1)). Subsequently, two additional subtypes of the neurotensin receptor (NTSR2 and NTSR3) and a candidate for NTSR4 have been identified. Development of subtype-selective neurotensin analogs facilitated investigations of the role of neurotensin receptors in mediating the effects of neurotensin.

Neurotensin Receptor Subtypes

Neurotensin exerts its effects primarily through two neurotensin receptor subtypes, NTSR1 and NTSR2. NTSR1 is a high-affinity (Kd = 0.1–0.3 nM) neurotensin receptor which is not sensitive to levocabastine, a nonpeptide H1 histamine antagonist. NTSR2 has a low affinity (Kd = 3–5 nM) for neurotensin and is sensitive to levocabastine. Both NTSR1 and NTSR2 are 7-transmembrane G-protein-coupled receptors (GPCRs). The human NTSR1 gene, encoding a 418 amino acid protein, is located on the long arm of chromosome 20 (20q13). The human NTSR2 gene encodes a 410 amino acid protein and is located on chromosome 2 (2p25.1). Separate NTSR subtypes display distinctive tissue distribution patterns (Table 1). NTSR1 is distributed widely throughout the CNS and is also found in the small and large intestines as well as the liver. NTSR2 is located more diffusely in the CNS than NTSR1. Two additional receptors have been shown to bind neurotensin among other ligands. Both receptors are single transmembrane domain receptors of the type I family. The NTSR3 is the intracellular sorting protein sortilin that interacts with multiple ligands including neurotensin, low-density lipoprotein (LDL), lipoprotein lipase (LPL), and progranulin. The human sortilin 1 (SORT1) gene, encoding an 831 amino acid protein, is located on the short arm of chromosome 1 (1p21.3-p13.1). NTSR3/sortilin, like NTSR1, binds neurotensin with high affinity once converted to its mature form upon cleavage. Sorting protein-related receptor (SorLA, also known as LR11) has been proposed as a fourth neurotensin receptor. The human SorLA gene, encoding a 2214 amino acid peptide, was mapped to chromosome 11 (11q 23.3–24). NTSR3/sortilin and SorLA/LR11 are located primarily in the CNS but also in nonneuronal tissues (Table 1, Vincent et al. 1999; Dobner 2005; St-Gelais et al. 2006).
Neurotensin Receptor (NTSR), Table 1

Tissue distribution of neurotensin receptors

NTSR1

NTSR2

NTSR3/sortilin

SorLA/LR11 (NTSR4)

CNS

CNS

CNS

CNS

Anterior pituitary

Anterior pituitary

Thyroid gland

Kidney

Autonomic nervous system

Upper gastrointestinal tract

Heart

Ovary

Enteric nervous system

Heart

Adrenal gland

Testis

Gastrointestinal tract

Pancreas

Pancreas

Lymph node

Carotid body

Adipose tissue

Liver

Skeletal muscle

Placenta

Testis

Signal Transduction of NTSR Receptors

Stimulation of NTSR1 leads to the activation of multiple signaling pathways. The major signal transduction event associated with the activation of NTSR1 is the stimulation of phospholipase C (PLC), which is responsible for the production of inositol 1,4,5-triphosphate, mobilization of Ca2+, and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a member of mitogen-activated protein kinase (MAPK) in a variety of tissues and cells. Neurotensin-induced ERK1/2 activation is also mediated via the activation of small GTPase Ras protein and epidermal growth factor receptor (EGFR) in human colonial epithelial cells. NTSR1 activation stimulates nuclear factor kappaB (NF-κB) which is dependent on intracellular calcium release. Neurotensin activates the Rho family proteins RhoA, Rac1, and Cdc42, and neurotensin-induced NF-κB activation, but not ERK1/2 activation, is mediated through the activation of RhoA, Rac1, and Cdc42. Little is known about the signaling pathways activated by the other three receptor subtypes. When NTSR2 is challenged with neurotensin, internalization of receptor–ligand complexes occurs through the activation of ERK1/2. Stimulation of NTSR3/sortilin activates ERK1/2 and phosphoinositide 3-kinase (PI3K)-dependent pathways in microglial cell lines (Martin et al. 2005; Zhao and Pothoulakis 2006; Ferraro et al. 2009). Homodimer and/or heterodimer of GPCRs play important roles in receptor trafficking, agonist binding, and signal transduction. Heterodimerization/oligomerization alters receptor functions by forming new receptor complexes that exhibit ligand-binding properties distinct from monomeric receptors. NTSR1 and NTSR2 can form heterodimers, and NTSR2 suppresses neurotensin-induced NTSR1 activity (Hwang et al. 2009). Additionally, NTSR1 forms heterodimers with other receptors such as apelin receptor and kappa opioid receptor. Formation of these heterodimers may provide additional functional resources to the cells.

Physiological Relevance of CNS NTSR Signaling

Neurotensin-containing neurons are neuroanatomically associated with the brain dopamine system, and neurotensin acts as a neuromodulator of dopaminergic transmission in several areas of the brain, including the nigrostriatal and mesolimbic pathways. Neurotensin increases the activity of dopaminergic neurons and dopamine release by antagonizing dopamine D2 receptor function through NTSR1-mediated increases in intracellular Ca2+ and an interaction between NTSR1 and D2 receptors. Neurotensin levels are increased, and NTSR1 mRNA levels are lower in the substantia nigra of Parkinson’s disease patients than in controls. Treatment with neurotensin analogs reduces tremor and muscle rigidity in animal models of Parkinson’s disease. These findings argue for the possibility that enhanced signaling through the substantia nigra NTSR1 supplements dopaminergic agonists to augment the function of the remaining dopaminergic neurons in Parkinson’s disease. However, activation of NTSR1 by neurotensin enhances N-methyl-D-aspartate (NMDA)-induced increase in extracellular glutamate levels. The neurotensin-mediated potentiation of NMDA receptor signaling may be mediated by phosphorylation of the NMDA receptors by protein kinase C. Glutamate is the major excitatory neurotransmitter, and the excessive activation of glutamate receptors, especially NMDA receptors, has been postulated to contribute to the neuronal injury. In cultured dopaminergic neurons, neurotensin enhances the neurotoxic effects of glutamate on dopaminergic neurons via NTSR1 activation. Thus, treatment with selective NTSR1 antagonists may be beneficial in improving the symptoms of Parkinson’s disease (Antonelli et al. 2007; Mustain et al. 2011). Abnormal neurotensin-NTSR1 signaling has been also found in the brain of Alzheimer’s disease patients. Regardless of whether CNS neurotensin-NTSR1 signaling is beneficial or deleterious in neurodegenerative processes, this signaling pathway is likely to be involved in the etiology of neurodegenerative diseases.

Centrally administered neurotensin causes a variety of effects similar to those exhibited by antipsychotic drugs. Reduced signaling capacity through NTSR1 contributes to psychotic symptom in schizophrenia. Cerebrospinal fluid levels of neurotensin are lower in schizophrenic patients than in control subjects, whereas increased levels of neurotensin are associated with improvement in symptoms during treatment. The density of neurotensin receptors (primarily NTSR1) is decreased in the intermediate entorhinal cortex of schizophrenia patients. Both NTSR1-deficient mice and NTSR2-deficient mice show schizophrenia-like signs, such as amphetamine-induced hyperlocomotion and lower basal glutamate levels. The lack of neurotensin causes diminished prepulse inhibition (PPI), a schizophrenia-like sign, while NTSR1 deficiency does not alter PPI and NTSR2-deficient mice have elevated PPI (Mustain et al. 2011). These findings support the idea that enhanced neurotensin-NTSR signaling is beneficial in improving schizophrenia symptoms. It is presently unclear what NTSR subtype is involved in this process. Brain-region-specific alterations in neurotensin-NTSR signaling may play a role in the etiology of schizophrenia.

Neurotensin has analgesic effects that are μ-opioid independent. Although NTSR2 was initially considered as a main receptor subtype mediating the antinociceptive effect of neurotensin, NTSR1 is also involved in neurotensin-induced analgesia. Both NTSR1 and NTSR2 are required for different aspects of neurotensin-induced analgesia, and these two receptors modulate the pain-induced behavior responses by suppressing activity of distinct spinal and/or supraspinal neural circuits (Dobner 2005; St-Gelais et al. 2006; Roussy et al. 2009).

CNS neurotensin-NTSR signaling plays a role in neuroendocrine function via modulation of the activity of the hypothalamus–pituitary axis. Neurotensin stimulates secretion of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH) and inhibits thyroid-stimulating hormone (TSH) secretion. Hypothalamic action of neurotensin increases prolactin secretion, while neurotensin action on the adenohypophysis causes a reduction in prolactin secretion. The direct hypothalamic effect of neurotensin in reducing prolactin secretion may be mediated by dopamine release into the portal system. It is unclear whether these effects of neurotensin are mediated via NTSR1 and/or NTSR2. Both receptors are expressed in the hypothalamus and anterior pituitary. Neurotensin has been implicated in the mediation of the preovulatory positive feedback of estradiol on GnRH release via NTSR2 activation. NTSR2 also mediates neurotensin-induced increase in CRH and corticosterone secretion in response to stress (Lafrance et al. 2010; Stolakis et al. 2010; Mustain et al. 2011).

Neurotensin participates in the regulation of metabolism. Central administration of neurotensin reduces food intake via NTSR1. NTSR1 mediates effects of other anorexigenic hormones, leptin and xenin. NTSR1 is also involved in hedonic feeding by mediating the hypothalamic leptin – mesolimbic dopamine system (Opland et al. 2013). Genetic deletion of NTSR2 did not cause any metabolic abnormalities in mice, while NTSR1-deficient mice have increased body weight, food intake, and adiposity, implicating NTSR1 in metabolic regulation (Mustain et al. 2011).

Neurotensin contributes to thermoregulation. CNS action of neurotensin reduces body temperature. NTSR1-deficient mice have increased body temperature and do not respond to the hypothermic effect of neurotensin, implicating neurotensin-NTSR1 signaling in thermal control.

Physiological Relevance of Peripheral NTSR Signaling

The effects of neurotensin in the gastrointestinal tract are mediated by both neural and hormonal mechanisms. Neurotensin elicits a relaxing effect on duodenal longitudinal muscle and induces contraction of the ileal muscle and the proximal colon. These neurotensin-induced alterations in gastrointestinal motilities were blocked by NTSR1 antagonist and were absent in NTSR1-deficient mice. Neurotensin-related peptide, xenin, also affects gastrointestinal motility partly via activation of NTSR1. These findings indicate that neurotensin regulates gastrointestinal motility via NTSR1 (Zhao and Pothoulakis 2006).

Neurotensin-NTSR1 signaling is associated with the progression and differentiation of tumors. NTSR1 is expressed in tumors of the ovary, pancreas, colon, prostate, and breast. High NTSR1 expression is associated with a larger tumor size, and the size of tumor becomes smaller in the presence of NTSR1 antagonist. In human breast cancer cell lines, functionally expressed NTSR1 receptor coordinated a series of transforming events, including cellular migration and invasion. The NTSR1 gene is a target of oncogenic pathways known to activate genes involved in cancer cell proliferation and transformation. When NTSR1 is challenged with neurotensin, a variety of signaling pathways are activated. For example, activation of NTSR1 promotes growth of colon tumors through NF-κB activation. Neurotensin also increased the activity of PI3K signaling by increasing specific microRNA species via NTSR1 in colon epithelial cells. During prolonged neurotensin agonist stimulation, NTSR1 receptors are recycled to the cell surface, leading to the long-term activation of ERK1/2, an oncogenic signaling pathway. Activation of NTSR1 by neurotensin leads to the activation of EGFR/EGFR2 (also known as HER2) signaling, contributing to breast cancer growth and metastasis. Neurotensin–NTSR1 signaling enhances epithelial-to-mesenchymal transition and promotes tumor metastasis by activating the Wnt/β-catenin signaling pathway in hepatocellular carcinoma (Ye et al. 2016). These findings place NTSR1 at a major nexus between neurotensin and tumorigenesis.

Physiological Relevance of Non-GPCR NTSRs

Whereas both NTSR3/sortilin and SorLA/LR11 are capable of binding neurotensin, the physiological relevance of these receptors is largely unclear. NTSR3/sortilin is predominantly expressed in regions of the CNS. Autism is a neurodevelopmental disorder and microglia are activated in the brains of patients with autism. NTSR3/sortilin is expressed in microglia and mediates neurotensin-induced chemokine release from human microglia through activation of mammalian target of rapamycin (mTOR) signaling (Patel et al. 2016). Thus, activation of NTSR3/sortilin may be involved in the pathogenesis of autism. NTSR3/sortilin binds not only neurotensin but also other ligands such as the receptor-associated protein (RAP), LPL and nerve growth factor precursor (proNGF) (St-Gelais et al. 2006). It is thus possible that NTSR3/sortilin subserves non-neurotensin-related functions in the CNS. Recent studies suggest that NTSR3/sortilin plays a role in the regulation of cognition, metabolism, and pathogenesis of cardiovascular disease. Levels of NTSR3/sortilin mRNA and protein were reduced in adipose tissue and skeletal muscle of obese mice and patients. NTSR3/sortilin promotes the formation of insulin-responsive glucose transporter 4 (GLUT4) storage vesicles in adipocyte cell line. Palmitate reduces the expression of NTSR3/sortilin in adipocytes and skeletal muscle cells (Tsuchiya et al. 2010). NTSR3/sortilin deficiency protects mice from high-fat diet-induced metabolic impairments by improving insulin sensitivity (Rabinowich et al. 2015). These findings suggest that NTSR3/sortilin plays a role in glucose homeostasis by modulating GLUT4 trafficking in adipose tissue and skeletal muscle and mediates FFA-induced insulin resistance in these tissues. Additionally, NTSR3/sortilin is also present in several types of cancer cells (St-Gelais et al. 2006; Bakirtzi et al. 2011; Mustain et al. 2011). However, the precise role of NTSR3/sortilin in cancer is presently unknown.

It has been suggested that SorLA/LR11 regulates the processing of the amyloid precursor protein and levels of SorLA/LR11 are reduced in the brains of Alzheimer disease patients, suggesting a possible role of SorLA/LR11 in the pathogenesis of this disease (Andersen et al. 2005).

Summary

Neurotensin exerts diverse actions through NTSR receptors in the CNS and in the periphery. Alterations in NTSR signaling have been implicated in a wide range of pathologic conditions such as schizophrenia, Parkinson’s disease, metabolic disorders, and cancer. Signaling pathways involving NTSR receptors and their downstream mediators could be potential drug targets for the treatment of these impairments. Pharmacological tools and genetically engineered animal models enabled us to manipulate NTSR signaling, and we have begun to elucidate specific role for each NTSR subtype. Creation of animal models with cell type-specific ablation of specific NTSR subtype should help clarify the role of NTSR subtypes in the mediation of neurotensin action. Development of additional subtype-selective agonistic and antagonistic neurotensin analogs that cross the blood–brain barrier may offer new avenues for the treatment of disorders associated with altered NTSR receptor signaling.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Physiology and PathophysiologyUniversity of ManitobaWinnipegCanada