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Neurotensin and Neurotensin Receptors in Health and Diseases: a Brief Review

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Neurotensin and Neurotensin Receptors in Health and Diseases: a Brief Review Indian Journal of Biochemistry & Biophysics Vol. 54, February-April 2017, 7-23 Neurotensin and Neurotensin Receptors in health and diseases: A brief review Sankar P Mitra* Department of Surgery, Division of Urology, University of Massachusetts Medical School 55, Lake Avenue (North), Worcester, MA 01655, USA Received 17 December 2015 ; revised 18 January 2017 Neurotensin (NT), a thirteen amino acid peptide is located primarily in the brain/central nervous system (CNS) and intestine. In brain or CNS, NT acts as a neurotransmitter/neuromodulator whereas in the digestive or gastrointestinal (GI) tract it works like a hormone. The peptide is processed differentially from its precursor in CNS and GI tissues. As a neuromodulator it controls several neuronal actions influencing dopaminergic, GABAergic, serotonergic, glutaminergic and cholinergic neurons. The peptide has a significant role in Schizophrenia, Parkinson disorder, Alzheimer’s disease, pain/analgesia, eating disorder, tumor growth and inflammation. It also exerts its influences by interacting with itscorresponding receptors. Until now three types of NT receptors (NTR- 1, NTR-2 and NTR-3) are identified for most physiologic effects. Among them, NTR-1 and NTR-2 are the typical G-protein coupled receptors (GPCR) with seven transmembrane (7TM) spanning the cell surface bi-layer whereas NTR-3 is a single transmembrane receptor belonging to the Sortilin family. The recent attention relating to NT-NTR interactions is drawn for several of its important physiologic role in health and diseases. Among them, neurological, analgesic and malignancy are considered to be the major concern. Keywords: Alzheimer disease, Analgesia, cAMP, Cancer, cGMP, Dopamine, G-protein, G-protein coupled receptor, Intracellular calcium, IP 3, Neurotensin, Neurotensin receptor, pain, Parkinson’s disease, Schizophrenia, Sortilin General features of Neurotensin : peptide acts as a neuro-transmitter conducting inter- Multitude of information are collected on NT, a tri- cellular and inter-neuronal signal processing like the decapeptide (<pQLYENKPRRPYIL-CO 2H) isolated previously known vaso-active amines (Serotonin, 1 from the bovine hypothalamus and intestine .The Dopamine, Nor-epinephrine, Catecholamine, Histamine, and Acetyl-choline, etc). Before the advent of NT and __________ *Correspondence: other peptides, those amines are considered as being the Phone: 508-752-3554 only neuronal signaling agents. Along with the E-mail: [email protected] discovery of NT, a long array of neuro-peptides Abbreviation : AA, Amino acid; AD, Alzheimer disease; CA, appeared on the scene and later recognized to be in the Central amygdala; cAMP, Cyclic adenosine mono-phosphate; CCK, Chole-cystokinin; cGMP, Cyclic guanosine mono- family of neurotransmitters. The sequential and phosphate; CNS, Central nervous system; CRH, Corticotropin phylogenetic study revealed that NT is well conserved releasing hormone; CSF, Cerebo-spinal fluid; DA, Dopamine; within the most mammals like bovine, dog, rat, and DTPA, Di-ethylene-tri-amine pentacetate; EC, Entorhinal cortex; human. For non-mammalian species, some changes ER, Endo plasmic reticulum; GABA, Gamma amino butyric acid; have occurred as noticed in the case of chicken GC, Guanylate cyclase; GDP, Guanosine di-phosphate; GF, 2,3 Growth factor; GH, Growth hormone; GHRH, Growth hormone (<pQLHV NKARRPYIL-CO 2H) . The genetic releas ing hormone; GI, Gastro intestine; GP, Globus palladus; mapping finds the location of NT to be within a GPCR, G-protein coupled receptor; GTP, Guanosine tri- chromosome, q12 for the human 4. Incidentally, the NT phosphate; HC, Hippocampus; MPTP, 1-Methyl-4-phenyl- mRNA can be induced in the brain by caffeine, 1,2,3,6-tetrahydropyrolidone; MTX, Methotrexate; NA, Nucleous Staurosporine, Sigma receptor antagonists or even by the accumben; NMDA, N-methyl D- aspar tate; NMN, Neuromedin 5,6 N; NT, Neurotensin; NTR, Neurotensin receptor; PD, Perkinson’s osmotic stimulation . Concerning its physical nature disease; PGA, Preaqueductal grey area; PI, Phosphoinostide; PRL, according to AA sequence, the peptide is significantly Prolactin; PLC, Phospho lipase C; PP, Pro-peptide; PTx, Pertussis basic for holding - KXRR- (X = P/A) patch within the toxin; RNAi, Inhibitory ribo-nucleic aci d; RVM, Rostro mid-region. The structure factor analysis indicates that, - ventricular medulla; SCLC, Small cell lung carcinoma; SCLC, 8-13 Small cell lung carcinoma; SN, Substantia nigra; VTA, Ventral RRPYIL-CO 2H moiety (NT ) is crucial forthe 7 tagamental area. receptor binding and exerting any biologic events . Any 8 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017 minor changes within that sequence even switching – peripheral actions, if injected intravenously, NT CO 2H to –CONH 2 at the terminal endorstereo-chemical lowers the blood pressure, induces bradycardia, modification of any AA significantly alters the binding causes vaso-dilation and provokes cyanosis in affinity ( Kd) and capacity ( Bmax ) affecting the nature and pento-barbital anesthetized Sprague-Dawly rats. The intensity of physiologic actions 7. The intact peptide massive release of Histamine has been implicated in 1-13 1, 5, 16 (NT ) and several of itsmajor –CO 2H terminal most of these incidents . metabolites Inside the brain or CNS, NT’s existence is detected 4-13 6-13 8-13 (-NT , -NT & -NT ) are equipotent to exert any at high level within anterior pituitary and receptor mediated events both centrally and peripherally hypothalamus (Table 1).The peptide is storedin places 7 evoking endocrine and exocrine functions . The cDNA like NA and VTA along with the DA neurons within cloning reveals that NT precursor carries another neuro- mid brain also sometimes coexists with CCK 5,16,17 . It peptide, Neuromedin-N (NMN) within its sequence, is also found in the brain stem and spinal neurons 18,19 . which bears a bit of similarity (-KIPYIL -CO 2H) at the – Regarding neuro-endocrine behavior, it enhances the 8 20 CO 2H end . As a result, NMN cross-reacts (~30 %) with release of GF and PL . In mice brain, there is a rise 7 the NTR . Studies indicate that the NT/NMN precursor of NT mRNA expression during the postpartum undergoes differential post-translational processing in period 21 . Further, the peptide increases ACTH level 9 the CNS and intestinal tissues . In brain or CNS, NT and with simultaneous enhancement of glucose and NMN are processed simultaneously and stored inside cortisol in the serum 22 . But it also lowers the level of the synaptic vesicles within synaptosomes whereas for TSH, LH and thyroid hormone, T4. The effect is intestine, the precursor processes by releasing only the thought to occur possibly for its effect on NT molecule while creating a large fragment of 21 AA hypothalamic TRH and ACTH 23-26 . 9-11 bearing NMN sequence at the–CO 2H end (Fig. 1). As per gastrointestinal (GI) effect, NT allows Often the processing event is seen different also for contraction of the intestine, gall bladder, colon and the endocrine tumors where NT precursor is pancreas 27-32 . Its level (~10 pMol/L) rises ( ≥ 100 processed by releasing numerous metabolites along 12 pMol/L) in the circulation after ingesting a fatty meal. with the NT and NMN . The release is seen higher in case of unsaturated fatty General role of NT : Initially, several physiologic acids (linoleic, oleic) compared to its saturated properties of NT are acknowledged through the analogs 39 . The release occurs mostly from the GI exogenous central administration, letting to mucosal cells 30 . The released NT in circulation helps hypothesize its ability to induce narcolepsy, digestion by contracting the gall bladder enhancing 5 hypothermia and analgesia . Aside those effects, NT’s the bile flow to saponify lipoid matter in food 28-31 . role in behavioral aspects are also noteworthy. The Alongside, while contracting the pancreas it delivers – peptide induces anorexia and at a time increases the HCO 3 and lipase into the intestine to hydrolyze fats water intake capacity 5,13 . It enhances the sleeping time for easy and rapid absorption in the liver 31,32 . when animals are particularly anesthetized by the Additionally, the peptide also creates uneasy gastric barbiturate or ethanol 5. The incidence of low levels of reflux by relaxing the sphincter of esophagus 32 . The NT in CSF of schizophrenic patients compared to any intestinal NT content follows an order of: Ileum ≥ normal subjects shows that the peptide might have a Jejunum > Duodenum. The cells having NT are modulatory role in that disorder 14,15 . As per its located mostly within the mucosal layer of jejuno- Fig. 1 — Enzymatic cleavage sites during post-translational processing of NT/NMN precursor (169AA) in canine intestine and brain. In case of intestine, it processes to large size (20AA) NMN (75%) and normal NT whereas in the brain both peptides are processed as usual like 13 AA NT and 6 AA NMN. This differential behavior is somewhat unique and common for all the species. MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES 9 Table 1 — The level of NT and its relative distribution of different NTR mRNA inside rat brain Brain Areas NT (pMol/gm) NTR-1 NTR-2 NTR-3 Globus palladus < 10 3+ 0 1+ Caudate putamen 10 ↔ 50 n.d. n.d. n.d. Nucleus Accumbens 10 ↔ 50 n.d. n.d. n.d. Substantia nigra 10 ↔ 50 3+ 2+ 2+ Periaqueductal gray 10 ↔ 50 1+ 3+ 1+ Hypothalamus 10 ↔ 50 3+ 3 2+ Hippocampus < 10 1+ 3+ 3+ Pituitary < 10 n.d. n.d. n.d. Spinal cord dorsal horn 10 ↔ 50 n.d. n.d. n.d. Central amygdala 10 ↔ 50 3+ 0 2+ Ventral tagamental area 10 ↔ 50 3+ 1+ 2+ Entorhinal cortex n.d. 3+ 3+ 1+ illeal region 33 . At present, NT’s role in cardiovascular diseases ormalignancies is a big concern. Several studies indicate that the higher level of NT or precursor in fasting plasma could be linked to the increased incidences of cardiovascular and cancers for both men and women 34 . Interestingly, the pro- Neurotensin/NT precursor level in women (~109 pMol/L) is seen somewhat higher than the men (~99 pMol/L) 34 .
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