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 (
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 . Pioneering work by Jing Li et al . has recently established an actual connection between continuing presence of high levels of NT or its precursor in circulation and cardio-vascular diseases, Fig. 2—The major cleaving sites for NT and NMN during diabetes or obesity 35 .Using NT gene lacking mice enzymatic metabolism by endo and amino-peptidases. they have confirmed that the peptide enhances fat 42,43 absorption both in vivo and in vitro via NTR-1 and NTR-1 antagonist, SR48692 . NTR-3 leading to insulin resistance diabetes including In addition to those roles, more diverse and obesity. The incidences of malignancies like, prostate, complex role of NT is noted in the CNS. It is observed to be heterogeneously distributed throughout colon or breasts are also noticed since NT enables to 18,44 induce the growth effect. It has been already the CNS tissues . The levels are high within documented that NT provokes atrophy of the intestine hypothalamus, SN, VTA, CA, HC, NA, GP and and stomach 36,37 . In many endocrine tumors the higher septum. Due to its potent neuro-modulatory role, NT expression level of NT and NTR followed by its regulates many neuro-transmitting systems that are spontaneous secretion is seen to accelerate the dopaminergic, serotonergic, cholinergic, glutaminergic malignancies via autocrine or paracrine pathway 38,39 . or GABAergic by nature. By virtue of this nature, it But as a normal behavior, NT’s release after meal is imposes number of behavioral and electrophysiological + +2 necessary to modulate the gastric motility which effects to a different extent through the Na and Ca 44 perhaps helps maintain a healthy bowl. Except in the dependent releases . case of incidental appearance of an abnormal Metabolism of NT : In circulating plasma, the phenotype, it may induce tumorigenicity which can be free/released NT lasts ~1.4 min before being degraded perpetuated later by its further release from the tumor by the endo- or exo-peptidases 45 . The cleaving sites tissues. The growth effect is confirmed in several are identified to be between Arg 8–Arg 9, Pro 10 –Tyr 11 , endocrine tumors like prostate, colon, breasts, lung Tyr 11 –Ile 12 or Ile–Leu. The released metabolites are 44 and pancreas. In all the cases, NT and its active inactive –NH 2 terminal residues (Fig. 2). fragments (-NT 4-13 , -NT 6-13 or -NT 8-13 ) promote the Experiments made by steady infusion in aorta (200 growth in both cultured cells and implanted tumors pmol/Kg/hr) for ~1 h period shows that among all the inside the nude mice 38-41 . As for further validation, NT organs, kidney, intestine, liver and brain are majorly is seen to induce the DNA synthesis in CHO cells responsible for the disappearance of NT 1-13 or any of 46 expressing the NTR which is blocked by specific its active –CO 2H terminal metabolites .Out of them, 10 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017
kidney is seen to be heavily involved in the clearing receptors of NT have been identified that are widely of both basal and stimulated version of NT. Several distributed throughout the body. A large number of experiments regarding its metabolism indicate that them are located inside the brain/CNS tissues or NT can act as a local hormone working via autocrine spread along the digestive tracts or GI tracts. Among or paracrine pathway 47 . those receptors, the NTR-1 is associated with major Physiologic role of NTRs : So far three different physiologic effects regulating neurological, growth or any endocrine actions 16,48 . But a set of important events also proceed via the NTR-2 and NTR-3. For example, the NTR–2 is involved in inducing analgesia, hypothermia and other pain related parameters whereas NTR-3 helps cellular migration viz , receptor internalization and participating in the growth promoting act 16,49 . The recent discovery indicates that NT may provide a protective role toward the neuronal or peripheral cell death by offering anti-apoptotic actions which has a positive impact on controlling the Alzheimer Disease (AD) 50 . The majority of NT’s physiologic actions on CNS were established by exogenous introduction in pentobarbital anesthetized rats leading to hypotension, cyanosis and also prolonging the sedation time alongside inducing the hypothermia 5. Besides the
original peptide, several NT agonists are also Fig. 3—Neurotensin receptors. A) NTR-1 showing 7TM (T1 to 8-13 effective in inducing hypothermia or potentiating the T7) within the lipid bilayer. The agonist, NT binding domain action of narcosis. But in all the cases, anti- primarily comprises of T6, E3, and T7. The antagonist SR48692 blocks the space close to outside the cell surface wit hin the turn of cholinergic, anti-serotonergic or anti-noradrenergic 5 T4, T6, and T7.) drugs have failed to alter the effects . As for further action, the NT-NTR interaction can also create narcolepsy also. The induction of analgesia is seen only when NT is injected inside the PGA in brain. Table–1 shows the distribution of NTRs at different areas in mouse brain. NT employs several neuro- endocrine actions also which usually occur either by releasing or helping synthesize several pituitary hormones like, GRH, CRH, Somatostatin, Thyrotropin or Prolactin 5,51-55 .
General features of the NT receptors : The NTR was detected at first by high affinity 125 I–NT binding using the brain plasma membranes from various mammalian and non-mammalian tissues and later confirmed by the cDNA cloning and sequencing 56,57 . Besides the CNS, NTR was identified in other organs like liver, intestine, lung, kidneys and gall bladder including the mast cells and several circulating 7,58,59 immune cells . The three types of NTR (NTR–1, Fig. 3 B—Neurotensin receptors shows several differences NTR–2 & NTR–3) are seen responsible for central, between NTR-1 and NTR-2 concer ning their ligand binding sites. peripheral or any other physiologic actions 48,49,60 SR48692 acts as an agonist whereas NT behaves opposite, an (Fig–3). Besides the differences in sizes and AA antagonist to the NTR-2. (The picture is redrawn by modifying the publication of Vincent JP et al . Trends. Pharm. Sci.1999, Vol. sequences, those receptors bear vast dissimilarities 20. P302 -309) regarding structures and ligand binding characteristics MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES 11
The receptor displays high binding affinity 125 (Kd ~10–50 pM) toward I-NT and evokes biologic effects by activating versatile associated G- protein α– subunits 49,56,57 (Fig. 3A). The theory of molecular interactions suggest that by binding at the extracellular docking port, agonist molecule imposes structural perturbation of the receptor causing a free energy change and altering other thermodynamic parameters which subsequently initiates series of successive intracellular signaling events. Thus, extracellular ligand binding incidence disturbs the intracellular receptor’s domain that activates the receptor linked trimeric G protein(s) (G αβγ ) complex initiating a cascade of specific signaling episodes allowing dissociate the GDP bound (G α +
GDP) α subunit by exchanging with the cytosolic GTP Fig. 3—Neurotensin receptors C) NTR-3. The receptor belongs to transforming to G α + GTP complex. The incident the Sortilin family. About 5–10% of the total receptor is expressed enables to activate series of enzymatic processes which on the cell surface. It displays good affinity ( Kd ~0.1-0.4 nM) after the furin cleavage. in essence direct the cellular behavior. In general, the which is also reflected in their pharmacological dissociation of α subunit from GDP by intracellular GTP actions. As per similarity, both NTR-1 and NTR-2 brings down affinity state ( Kd) of the receptor thus belong to the GPCR super family, having usual seven restricting the agonist binding ability. Experiments trans-membrane (7TM) strands spanning the cell conducted in its support using isolated plasma surface lipid bi-layer with –NH terminal exposing membrane expressing NTR-1 proved the hypothesis. 2 The prior treatment with GTP or any non-hydrolysable outside and –CO 2H end is dipping inside the cytosol (Fig. 3A & B) 49,60,61 . In human, the NTR-1and NTR- 2 stable GTP analogs reduces the NT binding affinity ( Kd) and capacity (B max ) significantly, a common feature that genes are located respectively at chromosomes 20 and 7,63-68 2 whereas NTR-3 resides in the chromosome number is observed for all the GPCRs . 162 . Unlike others, NTR–3 is a straight chain poly- Concerning the ligand interactions, there are few peptide not belonging to the GPCR family having novelties associated with the NTR–1: A) Promiscuity of NTR-1 attachment to the G single transmembrane whose–NH 2 terminal protrudes α subunits outside the cell surface and –CO 2H terminal is + immersed inside the cytosol (Fig–3C). NTR - 3 is B) NT binding is susceptible to the Na ion and identified to be a member of Sortilin family whose C) Sensitivity toward the thiol (- SH) alkylating 69 ligand binding sites bear strong homology with the agents that inhibit the NT interaction . protein gp 95/Sortilin that regulates intracellular The compound SR48692 synthesized by Sanofi sorting and trafficking while influencing the cellular Researchers acts as a specific antagonist that efficiently 60,61 125 growth and apoptosis . The observed AA sequence inhibits the I-NT the binding ( Ki~20 pM) and several indicates that NTR-1 (424 AA, ~48 KD) is about 10 of its biologic and physiologic actions 7,64-69 (Fig. 4). AA larger than the NTR–2 (410 AA, ~45 KD) Regarding the generation of second messengers, it is whereas regarding molecular weight they appear to be recorded that NTenhances the intracellular ↑cAMP ↑ +2 closer. NTR–2 bears ~64 % sequential homology with level and often raises the cytosolic calcium ( [Ca ]i) the NTR–1 but both NTR-1 and –2 bears no also 48,49 . Additional reports further indicate that in homology with NTR–3. It is seen somewhat bigger in certain neuronal cells it elicits the intracellular size having the molecular weight of ~95 KD (3A, B & ↑cGMP level. The rise of intracellular ↑cGMP during C). Concerning the physiological roles, they also act NT - NTR-1 interaction is often associated with the 48,49,56,57,60 differently . prior formation of IP 3 which in fact also helps elevate ↑ +2 NTR–1:Receptor characteristics and G-protein(s) association : the level of [Ca ]i by releasing from the intracellular It is the most common and widely studied NT store. In neuronal cells, especially in the case of receptor . NTR–1 was identified and cloned Dopaminergic neurons, initial rise of intracellular ↑ +2 independently by many and from numerous sources. [Ca ]i activates Nitric oxide synthase (NOS) leading 12 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017
Fig. 4—The chemical structure of non-peptide NTR-1 antagonist SR 48692, UK-73093, PD156425, L-734836 and Levocbastine (H 1 125 antagonist) that binds to NTR-2 and competes with the I- NT binding (IC 50 ~10–50 nM). Levocabastine like NT can trigger the inward current while interacting with the NTR-2 expressed in xenopous oocytes. to the generation of NO which in turn stimulates NTR-272 . The NT binding with NTR-2 creates Guanylate Cyclase (GC) enhancing the level of phosphorylation of ErK1/2 due to the hydrolysis of PI ↑cGMP. Uniquely, the NTR-1 is able to associate which causes internalization of the agonist bound 49 with diverse G α subunits via different intracellular receptor as seen in rat brain . Interestingly in case of loops. As confirmed by the deletion and mutation NTR-2, the selective NTR-1 antagonist, SR48692 ↑ +2 studies that, when NTR-1 is expressed in CHO-K1 behaves as agonist elevating the (Ca )i which in a cells, its third intracellular loop tends to associate with surprising move is antagonized by the NT. It is the G qα which takes part in the hydrolysis of phospho- recorded that H1 antagonist, Levocabastine selectively 125 inositide (PI) through the activation of PLC producing inhibits the I-NT binding to NTR-2 (IC 50 = 10.0 +2 IP 3 that subsequently releases Ca from the nM). The receptor is seen to be constitutively active intracellular store of ER. Selective mutation of AA but NT has no role in this affair, instead, it within that loop wipes off that effect but retains the antagonizes the effect of agonists or inverse agonists ↑cAMP elevating ability 43,49 . Evidences indicate either fully or partially 73,74 . The exact underlying further that often NTR-1 can associate with the PTx pharmacology is not known. Structurally, NTR-2 sensitive, inhibitory G αi. Treating with PTx causes lacks N-glycosylation at the extracellular region 74 ribosylation of the G αi, which afterward lowers the NT unlike its NTR-1counterpart (Fig. 3B). binding and stimulated rise of cAMP 70 . As a distinctive feature, the multiple attachment of NTR-1 NTR–3: Nature, location, and signaling: Distinctively, NTR-3 is not exactly a cell surface receptor (Fig. 3C). with different G α subunits at a time is visible in many instances 49 .The reason remains unexplored. Needless Only ~5–10 % of the total number of receptors express extracellularly whereas the rests express to say, a great many physiologic actions occur via this 61,75 receptor for its larger existence in both neuronal and inside the cell . Attention is directed recently due non-neuronal tissues. to its intimate involvement in the events of neuronal functionality, mitogenicity and atrophy of the 61,76 NTR–2: Receptor’s actions and G-protein’s association : organs . It is a single transmembrane glycoprotein Compared to the type-1, NTR-2 displays lower located mostly inside the ER of Golgi apparatus, affinity ( Kd ~10–100 nM) although both belong to the therefore, does not belong to the GPCR family. Its GPCR family (Fig. 3B). The NT binding affinity is actions are different by nature. It mainly participates 61 seen even lower ( Kd~10µM) in the case of rat brain. in course of intracellular trafficking . It is established The associated G α with NTR-2 is identified as G αq that during NT induced receptor internalization, which hydrolyzes PI during interaction with NT. NTR-3 is pulled on the plasma membrane from its Unlike NTR-1, it is insensitive toward the Na + ion internal sources. The event seems prominent for those during 125 I-NT binding 49,67,71-73 . It is proven that, the cells or neurons expressing the other NTRs since presence of Asp at second intracellular loop makes other peptides fail in doing so 77 . The agonist binding + 72,73 many GPCRs to be Na sensitive (Fig. 3B). affinity of NTR-3 is moderately high ( Kd ~10-15 nM) Removing the Asp 113 by neutral AA like Gly or Ala at but when co-transfected with Furin and expressed in the second intracellular loop desensitizesNTR-1 COS-7 cells it shows a much high affinity + 75,76 125 toward the Na ion which is absent in the case of (Kd ~0.3 nM) . The receptor was detected by I- MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES 13
NT binding and after isolating from the CHAPS on cancer cell lines indicate that growth response by soluble human brain membrane using affinity NT requires mainly the NTR-3 but not NTR-1 chromatography showing the Mw~100KD. Later it although the antagonist SR48692 specific to NTR-1 has been cloned from the cDNA library of human inhibits the event 76 . The incidence implicates a possibility brain expressing 833 AA and displaying 100% of the existence of another unidentified subtype of NTR. sequential homology with gp95/Sortilin particularly 75 after the Furin-cleaving site . Besides human, it is Role of NT in neurological disorders also identified in mouse and rat brain neurons and is NT & NTR in schizophrenia and drug abuse : seen to be responsible for the NT induced receptor 60 Table 1 shows the presence of NT and NTRs in internalization . The studies demonstrated that some of the areas of mouse brain. It is proven that NT Sortilin/NTR-3 is synthesized as a precursor or pro- often coexists withthe DA neurons within VTA or NA protein which is afterward converted to the desired or SN of hypothalamus 5,17-19,44 . VTA expresses high form by Furin within the trans -Golgi network of ER. level of NTR and are heavily innervated with NT The cleaving by Furin releases 44 AA pro-peptide containing neurons 14 . The co-localization of NT in (PP) resulting in the creation of functional NTR-3. DA neurons and its subsequent interactions after Interestingly, this 44 AA PP efficiently resists the NT release bear immense significance concerning the binding therefore acts as a potent endogenous schizophrenia and other psychotic disorders and also inhibitor ( K ~20–30 nM). If no cleaving occurs by d simultaneous blocking of any hyperactivity produced Furin to eliminate the PP then NT fails to bind that by the psycho-stimulants like amphetamine or precursor of NTR-3. It is thus hypothesized that this cocaine 51,79-81 . Typically, greater than 80% of the DA 44 AA PP when attached might impose a steric 75 neurons express NTR-1 so the depolarization created hindrance while blocking the NT docking site . by NT may occur more frequently 51,80 . Inside the NA, The intracellular signalling via NTR-3 is seemingly NTR sits on both the pre and post-synaptic DA more complex than the others since a scanty portions receptors. At its pre-synaptic performance, NT blocks (~5–10 %) are located on the cell surface but that the D 2 auto-receptors by antagonizing the effect of might be enough to influence the internalization of DA thereby enhancing its release thus increasing the NT bound NTRs 61,75 . It has been noticed that in course firings of the DA neurons while also raising the of NT induced internalization of receptor(s), a process additional intracellular Ca +2 level by interacting with of hetero-dimerization occurs between NTR-1 and NTR-1. Due to this intimate connection between NT NTR-3 which is a common incidence in many and DA neurons and its subsequent neuro-regulatory carcinomas like in HT-29.The NT induced hetero- effect through their respective receptors, one can dimer complex after internalization activates the MAP speculate that NT or its agonists can be used as a kinase and hydrolyze PI which eventually results in therapeutic measure in treating the schizophrenia cell proliferation. The dimerization event does not which is supported by the fact that central change the binding characteristics of NT to NTR-1. administration of NT produces anti-psychotic effect51 . At this situation, the ratio of NTR-1/NTR-3 is Further, among the schizophrenics there is ~40% approximately 1/10 to 1/20. Being alone NTR-3 decrease of NTR in the EC and the overall NT levels cannot activate the MAP kinase or else hydrolyze the are always low in their CSF 15 . In drug free PI. On the other hand its presence somehow decreases schizophrenics also, the level of NT and its the efficacy of NTR-1 to stimulate the MAPK or PI metabolites are noticeably lower in CSF than any hydrolysis 78 . Like HT-29, a large section of epithelial normal subjects. Additionally, the levels also vary tumor cells belonging to lung, colon and prostate co- with the severity of disease. Treatment with anti- express NTR-3 along with the NTR-1. Intuitively, psychotic drugs often normalizes the levels in CSF 15 . their dual and synchronized action during intracellular It is thus envisaged that NT may act as a therapeutic signaling event exerts mitogenicity in vivo and in agent in treating this disorder since its central vitro 76 . Being alone NTR-3 only helps the normal administration induces anti-psychotic behavior 15,51 . growth as seen for intestine 76 . It could be a possibility The overall information so far indicates that DA that NT binding and subsequent internalization of transmission is often modulated by the NT either NTR-3 might trigger the release of unknown trophic directly or indirectly: a) by up-regulating the tyrosine factors that help express the normal growth. Studies hydroxylase (TH) mRNA in striatum thereby 14 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017
Table 2 — Several physiologically active analogs of NT which mainly act as agonists Analogs 1 2 3 4 5 6 7 8 9 10 11 12 13 NT p-Glu Leu Tyr Glu Asn Lys Pro Arg Arg Pro Tyr Ile Leu NT69L x x x x x x x N-Methyl-Arg Lys Pro neo-Trp tert-Leu Leu NT72 x x x x x x X x d-Lys Pro neo-Trp tert-Leu Leu NT77L x x x x x x x Arg d-Orn Pro neo-Trp tert-Leu Leu NT79 x x x x x x x N-Methyl-Arg Arg Pro d-3,1-Nal tert-Leu Leu enhancing the DA production or b) by lowering the binding of DA to the D 2 receptor which arises due to steric interference created during simultaneous DA-D2 and NT-NTR interactions which also eventually modifies the intracellular second messenger 82,84 generations . NTR’s existence is visualized in those nerve terminals which deepens inside the cell Fig. 5—The chemical conversion of MPTP (1-Methyl-4-phenyl- bodies and dendrites within SN and VTA 44 . It is 1,2,3,6 tetra-hydro pyridine) to MPP + (1-Methyl–4phenyl + mentionedalso that, NT opposes the DA effect in both pyridinium ion) by Mono-amine oxidase B (MAO-B). MPP is toxic and creates Parkinson like syndrome by disrupting dopamine pre- and post-synaptic path ways, which either producing neurons in SN. It inactivates the tyrosine hydroxylase. enhances or lowers the DA regulated transmission depending on locations inside the brain. But as a inside the basal ganglia. Importantly, it increases whole, NT- NTR-1 interaction and DA release has a glutamate induced excito-toxicity within the DA positive effect toward the anti-psychotic disorder 84,85 . neurons. In that way, NT-NTR-1 interaction As a further addition, NT can act as a psycho- modulates the effect created during NMDA receptor 89 stimulantalso which solely depends on the site of its activation . So it is logical to assume that NTR-1 administration. If injected inside the VTA, NT or its antagonists can be utilized in the course of PD therapy agonists act as a psycho stimulant increasing the which indeed shows a promising effect. locomotor action because that area expresses high It is noticed that in most PD affected patients the extent of NTR. Since NT colocalizes with the DA average NT level in plasma is ~2 fold higher than the 90 neurons so possibly rising DA level is thought to be normal control subjects irrespective of the sexes . It accountable for this event 51,84-87 . The experiments is also seen that NT immunoreactivity increases have proven this fact that if injected inside VTA, the within the SN of PD patients especially at zona 91 agonists enhance the hyperactivity by releasing DA compacta and zona reticulata (~2 fold). Studies inside NA. On the contrary, when brain permeable indicate further that the lesser amount of DA neurons agonists (NT69L) are injected within the NA, it and subsequent lesser expression of NTR-1 occur 92 lowers the responses of psycho-stimulants like D- within those areas for most PD patients . amphetamine or cocaine 86,87 . Therefore, endogenous Experiments on rats while inducing PD by applying 93 NT plays dual role acting as a natural psycho- MPTP (Fig. 5) produces the similar results . As per stimulant and also preventing the drug abuse. So, conclusion, there exists a definite correlation between stable and permeable NT agonists can be used for the NT-NTR and DA-D2 interactions in the disease. The later event by preventing or weakening any behavioral lesser functionality of NTR-1 is seen to occur due to sensitization produced by the psycho-stimulants like neuronal degradation which arises during the amphetamine or cocaine 88 . Table 2 shows several progression of PD. It could be a reason why the level active analogs of NT having modified AA at different of NT immunoreactivity in those tissues is seen positions of NT 8-13 . higher which also reflects its higher level in the CSF and plasma. It is hypothesized by Caceda et al. that it Role of NT and NTR in Parkinson’s disease (PD): is a part of compensatory mechanism why the NT The exact role of NT in PD is hitherto level is raised high because in that way motor undetermined but studies convince its potential role functions of the DA neurons are attempting to be on this locomotor disorder. It is already preserved 93 . It could be also a possibility that acknowledged that the peptide plays a significant role deregulations of neural transmission of NT may regarding neuroplasticity and neurodegeneration follow the other striatopallidal pathway. Experiments MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES 15
using the neuro-toxin (6-hydroxy-dopamine) showed response largely relies on a small group of patients that bilateral injection of NT in the medial forebrain but not for all 100 . It is noticed that NT and NTR bundle attenuates the muscle rigidity and tremor 94 . containing fibres are densely populated within EC of Similar results are obtained using the NT agonist the brain. This area is important for exhibiting (NT69L) during amphetamine or apomorphine learning and memory 101 . At the onset of AD it shows induced rotatory behavior 95 . But despite that fact, the some structural perturbations which is signified as role of NT enhancing the glutamate excito-toxicity in being the pathological evidence 102 . Studies at past DA neurons takes much precedence 89 . So the use of indicate that NT modulates cognition but the antagonists are thought to be a positive approach in mechanism stays unclear. According to the recent this concern. studies, NT-NTR-1 interaction increases firing
Role of NT and NTR in Alzheimer Disease (AD): frequency of the action potential which is afterward + Continuing decay of cognitive ability is the sole mediated by the down-regulation of TREK-2 K sign of AD 96 . Either to prevent the further decay or to channels. So, the micro-injection of permeable NT improve the detoriating cognitive function is a general agonist PD149163 (Fig. 7) inside EC enhances the approach regarding the disease’s therapy. The current spatial learning behavior when assessed by using the 101 treatments include choline esterase inhibitors Barnes Maze Test . This agonist causes a persistent (Donepezil, Rivastigmine, Exelon or the natural increase in the firing frequency of action potential product Physostigmine) or partial antagonist of which in turn helps the memory condition in APP/PSI Glutametargic NMDA receptor, Memantine 97-99 mice normally used as a model of AD. So NT and its 101 (Fig. 6). But the success is so far limited and lasts agonist exhibits beneficial role in the mouse model . only for a brief period of time. Additionally, the In the temporal lobe of AD patients the NTR-1 and NTR- 2 expressions are seen severely low in comparison to NT whereas the level of NTR-3 remains unchanged 103 . A study performed by Jansen et al have proven that the absence of NTR-3/Sortilin has a preventive role in age related neuronal degeneration but not in the course of developmental apoptosis 104,105 . It is observed that neurotensinergic system changes during aging or in any neuro- degenerative diseases like AD. The mechanismis unclear 104 . Regarding biochemistry, it is established that NTR-3/Sortilin can form heterodimer with the
neurotrophin receptors, eg, p75NTR, TrkA or TrkB to Fig.6—Chemical structure of several known drugs currently used trigger the cell death initiated by proNGF or 106,107 in the treatment of Alzheimer’s disease. proBDNF . The pro-NGF induced apoptosis is
Fig. 7—Chemical structure of non-peptide NTR-1 agonist PD149163, α2- adreno-receptor antagonist and Methyl sergide, antagonist toward 5HT 2B and 5HT 2C serotonin receptors. 16 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017
blocked either by a high dose of NT (10 µM) or the to be the important pain modulator as seen during the cleaved pro-domain peptide of pro-NGF (100µM) systemic administering of morphine 51 . On the other which can antagonize while competing with the hand, NTR-2 is seen to be involved in agonist induced binding site of NTR-3/Sortilin and pro-NGF 108-110 . analgesic effect both in thermal nociception and also Seemingly, the dose used for NT in the study shows during the writhing tests 118 . Introduction of effectivity only at the higher concentration (10 µM) Levocabastine blocks that NT induced analgesic but its average level in the brain is ~50 pM 110 . So the effect whereas the NTR-1 antagonist SR48692 fails in controversy arises whether in reality NT actually that performance identifying the specific involvement serves as a natural regulator. On the other hand, the of NTR-2 in this pain mediating event 119 . anti-apoptotic preventive role of NT has been Interestingly, NT79 a selective NTR-2 agonist is established by using the agonist JMV449 (1-10 nM) inactive in reducing the thermal pain but effective in while protecting the neurons like in the case of retinal reducing acetic acid induced writhing tests in rats. keratinocytes from illumination damage 111 .From Whereas PD149163 a selective NTR-1 agonist and overall perspectives, it is thus presumed that nonselective agonist NT69L both can reduce the pain endogenous NT could offer a protective role through level during inflammatory condition produced by the the anti-apoptotic behavior. Therefore in future, some formalin (Table. 2, Fig. 4). Those substances are also NT agonists can be used for the prevention of AD. effective in controlling the neuropathic pains 120 . Studies suggests that in near future, various NT analogs (Table. 2) NT in pain & analgesia can be used in treating the various pain situations NT & NTR in pain and analgesia: Judging by the (thermal, visceral and inflammatory conditions). But their dose-dependent anti-nociceptive action, NT or any of efficiencies would vary as per selectivity of the NTRs 51 . its stable analogs appears to be more potent than the morphine 51,112,113 . If injected at nano-molar doses Role of NT in cancer inside the RVM, it shows a good anti-nociception NT & NTR in malignancy: The NT-NTR interaction effect in response to the heat stimulus whereas, at in the field of cancer draws serious attention in terms of pico-molar doses it induces the opposite effect both cure and diagnosis. Numerous studies are on the facilitating spinal nociception reaction 114,115 . The way for a proper understanding of intracellular pathways dose-response curve indicates a possible role of two involved in the biology of NT-NTR interactions relating different types of NT receptors or the involvement of to malignancy 117 . It is established that NT offers growth two separate and diverse neuronal pathways 116 . to the normal and malignant cells both in vivo and in Uniquely, the anti-nociception effect induced by a vitro which is recorded for gastro-pancreatic cells, selective NTR-1 agonist, PD 149163 is partially prostate carcinomas, fibroblasts, hepatocytes, lung, 36-39,41 blocked by Yohimbine (α2 - adreno-receptor antagonist) adrenal carcinomas, pituitary adenomas etc . In and also by the Serotonin blocker, Methyl Sergide most cases either the NTR-1 or NTR-3 individually or (5HT 2B & 5HT 2C serotonin receptors) (Fig. 7). On the dually participate in the growth promoting role. Some other hand anti-nociception produced by the NTR-2 studies insist that NT- NTR-1 interaction is primarily agonist β–Lactotensin (-HIRL-CO 2H) is blocked only involved in the act of malignant growth. But recent by the Yohimbine. So, the activation of NTR-1 in works indicate that since NT prevents apoptosis via RVM induces anti-nociception by releasing both nor- NTR-3, so that may incite uncontrolled cell growth epinephrine and serotonin from the spinal fibres encouraging the proliferation of cancer 117,118 . The role of whereas the effect of NTR-2 is mediated only by the NTR-3 has been studied in detail for breast cancer cell nor-epinephrine release 51 . line (MCF-7), colorectal carcinoma (HT29) and pituitary The overall anti-nociception action mediated via adenomas 111,117,119,124 . As one may hypothesize, that the NTRs also depends on the nature of tests and species tissue specific expression of NT and NTRs offer a used during experiments. The involvement of NTR balance of normalcy under a healthy condition which regarding analgesia is surprisingly confusing 51 . becomes deregulated in the event of malignancy since Experiments conducted by using the NTR-1 gene NTRs often over expressed in many aggressive tumors lacking mice or inhibiting it by introducing antisense derived from various sources like pancreas, prostate, peptide nucleic acid proves hardly the role of NTR-1 colon, lung, mammary glands etc 38-41,119-124. . Instances in hot plate tests. But for same knockout mice, in emphasize that NT’s interaction with NTR-1 singularly formalin induced persistent pain, NTR-1 is identified or jointly with NTR-3 is liable for the progression of MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES 17
malignancies 119,120 . also, especially considering the results of in vitro As a normal occurrence, human epithelial studies 136 . Anyway, whichever pathways may be mammary cells do not express NTR-1 but in the case followed, SR48692 can efficiently block the growth of carcinomas, like MCF-7, the over expression of in most situations. The works on pituitary cancer NTR-1 along with NT turns the growth uncontrolled. indicate that in the case of functioning (hormone The activation of Gαq during interaction leads to secreting) pituitary adenoma the level of NT activate the PLC and later Protein Kinase C (PKC) expression is higher than the non-functioning or which is known to enhance the tumor growth. It has normal pituitary gland. The NTR-3 is seen to be been demonstrated also that synthetic NT agonist expressed in both adenomas but not in the case of JMV449 (H-KΨ(CH 2NH)-KPYIL-CO 2H) helps the normal pituitary tissue. Uniquely neither the NTR-1 cell-growth while inhibiting apoptosis via NTR-3 and nor NTR-2 mRNA is expressed in any adenomas or subsequently upregulating the expression of Bcl-2 normal pituitary gland. In this case NT may work via without decreasing the p53 level 118 . Besides the autocrine/paracrine pathway during interacting only growth effect, NT and its agonists assist the tumor with theNTR-3137 . progression through metastasis, helping the malignant It has been established that NT alone enhances the cells to migrate for further invasion 122 . Noticeably, DNA synthesis in many tumor cell lines including >90 % of the breast carcinoma expresses NTR-1. So, androgen independent PC3 38 . But uniquely, while depleting its expression either by treating with RNAi acting together with the β–agonist, Isoproterenol, NT or blocking the agonist’s interaction using SR48692 not only reverses the event and but also synergizes the shows significant positive responses in reducing the DNA lowering ability of isoproterenol 124 126 tumor progression . Similar effects are recorded in tremendously . In PC3, in addition to NTRs, β2– the case of androgen independent human prostate adreno-receptor receptor is over expressed and β2– cancer cell lines, PC3 38,120 . Unlike the PC3, LNCaP agonists alone lower the DNA synthesis 127 . But when expresses both NTR-3 and NT. 39,120 . These cells added with NT that lowering ability is highly undergo proliferation using own secretory NT synergized in a dose-dependent manner 128 . Other than 39,120 following autocrine pathway . But for the others, Isoproterenol, several β2-active anti-asthmatic drugs, cell growth may follow either endocrine or paracrine R-Albuterol or Formoterol ( RR - or RS -) produces the path 38,39 . In small cell lung carcinoma (SCLC), NT similar effect (Mitra SP, unpublished data). The offers growth possibly through the autocrine or excessive rise of intracellular cAMP during co- paracrine pathways since about 75% of human SCLC interaction is identified as being the leading cause cell lines express the NT mRNA 125 . Besides the behind this non-proliferative effect 126,128 . SCLC, ~75% human non-SCLC cells also express NTR-1 along with the NT 132 . Experiments conducted Uses of NT and its analogs on tumor (human SCLC-NCl-H209) bearing nude The importance of NT- NTR interaction in health is mice by orally administering the SR48692 caused evidently wide. Thus attempts are made to use either 99% reduction of the tumor growth 133 . Additionally, the NT or NTRs as a biomarker or for any other SR48692 inhibits the NT induced growth of human therapeutic purposes. For that matter, several stable analogs of NT, either the agonists or antagonists are colon carcinoma (SW480) also. In this cells NT 125 enhances the size and tumor volume by >250 % 134 . synthesized . The main obstacle to use NT as a biomarker or therapeutic measure is due to its rapid The human pancreatic adenocarcinoma (90% of all 129 human pancreatic cancers having 5 year survival rate degradation within thecirculation (t 1/2 ~2.3 min) . of 3–5%) expresses NTR-1 which is noticeably absent But identifying NTR within an appropriate gland or in the case of normal or tissues affected with chronic tissues which normally do not express can be utilized for the cancer prognosis, especially for several pancreatitis. As for diagnosis, the appearance of NTR 125 is thought to be the initiation of pancreatic cancers 135 . epithelial tumors . The stimulation by NT induces mitogenicity in It is noticed that agonism by NT displays beneficial MIAPaCa and PNC-1 cell lines derived from the role on the psychotic disorders whereas antagonism is human pancreas expressing NTR-1121 . Although indicative to the possible cure of tumor. Based on that direct involvement of NTR-1 is identified as being the fact, few stable agonists and antagonists are supreme cause but the role of NTR-3 is accounted constructed to combat mental/neurological disorders as also to cure the cancers. For example, the NTR-1 18 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017
Fig. 8—Chemical structure of new NTR-1 antagonist, RP66453 and NT4 conjugate, DTPA and Methotrexate. agonists (PD149163 & other non-peptide analogs) are conjugating at least four NT 8-13 sequences (RRPYIL) seen useful to treat the psychotic illnesses on the other in certain ways which can be chemically linked to hand, antagonist, SR48692 displays anti-tumor many tumors destroying cytotoxic agents 125,132 property 51,88,117 (Table. 2, Fig. 4 & 7). Several (Fig. 8). This dendrimeric peptide is stable in human antagonists are on trial to be employed for treating the plasma for ~24 h at 37°C 132 . If linked to the DTPA or cancers. In that regard, new antagonists belonging to any other radio nuclides ( 111 In, 99m Tc, 188 Re or 18 F) the category of peptidomimetics or cyclic-peptides, an then those probes could be used for both imaging and aromatic compound like RP66453 or a secondary therapeutic needs 133 . It has been reported that the metabolite of macrocycle antibiotics Vancomycin covalently linked NT4 dendrimer with MTX can (from the Actinomycetes strain A9738) are reduce the tumor volume >60% while lowering the synthesized or isolated (Fig. 8). Concerning the side effect of MTX to a significant extent 132 . As a selectivity, later one binds to the guinea pig ileum further strategy, often the peptides are also covalently with high affinity (IC 50 ~30µg/mL) expressing NTR-1 attached to the surface of lipid nano-carriers pre- without interacting with NTR-2138 . loaded with the toxic drugs inside. This also enhances In addition to the medicinal uses, attempts are also the bioavailability as well as the concentration of drug made to exploit the event of NT-NTR interaction for regimens at the desired sites 134 . Until now, majority of molecular targeting 125,130 . On that accord, toxic drugs the probes are made for targeting the NTR-1 but there like Methotrexateor any imaging substances are are others which can interact with the type-3 NTR chemically conjugated to any stable NT analogs for since in most carcinomas both receptors are often direct delivering to the tumor either for healing or expressed. The event of heterodimerization of imaging purposes 132,133 (Fig. 8). The process enhances NTR-1 & 3 and subsequent internalization of the the bioavailability as well as permeability of the agonist bound hetero dimer helps the process of conjugates allowing cross the blood-brain barrier. imaging and therapeutic ability. Thus by creating a lipophilic magic bullet, it is targeted directly to the diseased tissues Conclusion simultaneously avoiding any adversarial effects 125,134 Besides acting as neuropeptide displaying toward the healthy organs . numerous neuronal effects, NT also influences effects To enhance the stability and enabling to cross the on a number of non-neuronal tissues. Those actions CNS barrier, a modified lysine substituted cyclic NT insist to find many of its behavior, tissue specific dipeptide (c
some of its biochemical and patho-physiological Peptides , 1 (1980) 159. behavior. To better identify its role in normal and 4 Marondel I, Renault B, Lieman J, Ward D & Kucherlapati R, Physical mapping of human Neurotensin gene between diseased conditions, a number of NT mimetics are markers D12S1444 and D12S81 on chromosome 12q21. constructed acting either as agonists or antagonists, Genomics , 38 (1996) 243. which are currently in the process of being used in 5 Bisette G & Nemeroff C B, The neurobiology of Neurotensin.In: course of diagnosis or therapeutic needs. The peptide Psycho-pharmacology – 4th generation of progress by American is modified to ensure more stability, bioavailability college of Neuro-psychopharmacology (Ed Bloom FE & Kupfer DJ Raven Press, New York, NY) 1990. and also enabling it to cross the blood-brain barrier. 6 Svenningsson P, Georgieva J, Kontny E, Heilig M & NT or any of its peptide - mimetics are introduced to Fredholm B, Involvement of a c-fos-dependent mechanism in act as magic bullets for targeting the diseased organs caffeine induced expression of preprotachykinin A and to deliver the toxic drug regimens. The selective Neurotensin / Neuromedin N gene in rat striatum. Eur J targeting would certainly lower the undesirable side Neurosci , 9 (1997) 2135. 7 Mitra SP, Binding chemistry and molecular heterogeneity of effects. Basing on that notion, several new drugs are Neurotensin binding protein(s) / receptor in adult chicken constructed to cure the schizophrenia, chronic pain, tissues. Indian J Biochem Biophys , 50 (2013) 511. alcoholism and others. 8 Dobner PR, Barber DL, Villa-Komaroff L & McKiernan C, Aside its future uses, one biochemically Cloning and sequence analysis of cDNA for the canine Neurotensin / NeuromedinN precursor. Proc Natl Acad Sci intriguing part is the differential processing nature (USA) , 84 (1987) 3516. of NT precursor in neuronal and non-neuronal 9 Carraway RE, Mitra SP & Spaulding G, Post-translational tissues. Obviously, the event follows natural processing of the Neurotensin / NeuromedinN precursor. Ann demand. But the inherent cause behind this event N Y Acad Sci , 668 (1992) 1. stays unexplained which may reveal many of the 10 Carraway RE & Mitra SP, Differential processing of Neurotensin and NeuromedinN precursors in canine brain unidentified physiologic roles played by NT. and intestine. J Biol Chem , 265 (1990) 8627. Further the differential level of expression of 11 Carraway R E & Mitra S P, The use of RIA to compare the various NTRs in neuronal and non-neuronal tissues tissue and subcellular distributions of Neurotensin and is not thoroughly investigated. The downstream NeuromedinN in the cat. Endocrinology , 120 (1987) 2092. signaling and subsequent feedback effects 12 Carraway RE, Mitra SP, Feurle GE & Hacki WH, Presence of Neurotensin and NeuromedinN within common precursor involving other signaling molecules need further from human pancreatic neuroendocrine tumor. J Clin study to offer more clarity to better understand Endocrinol Metab , 66 (1988) 1323 . about the diseases and disorders. Additionally, the 13 Tremblay M, Rouillard C & Levesque D, Dopamine D 3 exact role of NTR-2 is also not fully well receptors antisense neuropeptide mRNA levels in rat nucleus established. accumbens. Neuroreport , 8 (1997) 3901. 14 Kinkead B & Nemeroff CB, Neurotensin: An endogenous Further, the importance of NTR-3 either alone or in anti-psychotic? Curr Opin Pharmacol , 2 (2002) 99. combination with others is not completely identified. 15 Sharma RP, Janiack PG, Bisette G & Nemeroff CB, CSF The uniqueness of NTR-3 belonging to the family of neurotensin concentrations and anti-psychotic treatment in Sortilin opens up a crucial chapter about the role of Scizophrenia and Scizo-affective disorders. Am J Psychiat , NT in tumor progression and also the age related 154 (1997) 1019. 16 Tyler-McMahon BM, Boules M & Richelson E, Neurotensin: neurological disorders like AD. Peptide for the next millennium. Regul Pept , 93 (2000) 125. 17 Seroogy KB, Mehta A& Fallon JH, Neurotensin and CCK Acknowledgement coexistence within neurons of the ventral mesencephalon: The author gratefully acknowledges sincere help provided projections to forebrain. Exp Brain Res , 68 (1987) 277. by Dr Rajesh Kumar Barur, University Of Massachusetts 18 Shipley MT, Mclean JH & Behbehani MM, Heterogeneous Medical School Worcester, during library work. distribution of neurotensin-like immunoreactive neurons and fibers in the midbrain periaqueductal gray of the rat. References J Neurosci , 7 (1987) 2025. 1 Carraway RE & Leeman SE, The isolation of a new 19 Beitz AJ, The sites of origin of brain stem Neurotensin and hypotensive peptide, Neurotensin, from bovine serotonin projections to the rodent nucleus raphe magnus. hypothalamus. J Biol Chem , 248 (1973) 6854. J Neurosci , 2 (1982) 829. 2 Carraway RE, Ruane SE & Kim HR, Distribution of 20 Maeda K & Frohman LA, Dissociation of systemic and Neurotensin like material in representative vertebrates and central effects of Neurotensin on the secretion of Growth invertebrates: apparent conservation of – CO 2H terminal Hormone, Prolactin and Thyrotropin. Endocrinology , 103 region during evolution. Peptides , 3 (1982) 115. (1978) 1903. 3 Carraway RE & Bhatnagar YM, Immunochemical 21 Driessen TM, Zhao C, Whittlinger A, Williams H & Gamie characterization of Neurotensin like peptides in chicken. SC, Endogenous CNS expression of Neurotensin and 20 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017
Neurotensin receptors is altered during postpartum period in Neurotensin on intestinal mucosa: not just trefoil peptides. outbred mice. Plos-One , 9 (2014) e83098. World J Gastroentrol , 14 (2008) 3602. 22 Nicot A, Berod A, Gully D, Rowe W, Quirion R & Ron de 38 Seethalakshmi L, Mitra SP, Dobner PR & Carraway RE, Kloet E, Blockade of Neurotensin binding in rat Neurotensin receptor expression in prostate cancer cell lines hypothalamus and central action of Neurotensin on the and growth effect of NT at physiological concentrations. hypothalamic – pituitary – adrenal axis with non-peptide Prostate , 31 (1997) 183. receptor antagonists. Neuroendocrinology , 59 (1994) 572. 39 Sehgal I, Powers S, Huntley B, Powise G, Pihelkow M & 23 Gudelsky G A, Berry S A & Meltzer H Y, Neurotensin Maihle N, Neurotensin is an autocrine trophic factor activates tubero-infundibular dopamine neurons and stimulated by androgen withdrawal in human prostate cancer. increases serum corticosterone concentrations in the rat. Pro Natl Acad Sci (USA) , 91 (1994) 4673. Neuroendocrinology , 49 (1989) 604. 40 Barber DL, Cacace AM, Raucci DT & Ganz MB, Fatty acids 24 McCann SM, Vijayan E, Koenig J & Krulich L, The effects stereospecifically stimulate Neurotensin release and increase +2 of anterior pituitary hormone secretion. Ann N Y Acad Sci , ↑[Ca ]I in enteric endocrine cells. Am J Physiol , 261(1991) G497. 400 (1982) 160. 41 Carraway RE & Plona AM, Involvement of Neurotensin in 25 Fuxe K, Agnati LF, Anderson K & Eneroth P, Studies on the cancer growth: evidence, mechanisms and development of Neurotensin–Catecholamine interactions in the hypothalamus diagnostic tools. Peptides , 27 (2006) 2445. and in the forebrain of the male rat. Neurochem Int , 42 Cusack R, Chou T, Jansen K, McCormick DJ & Richelson E, 6 (1984) 737. Analysis of binding sites and efficacy of a species-specific 26 Wolffe RR, Allsop JR & Burke JF, Increased glucose peptide at rat and human Neurotensin receptors. J Peptide production following Neurotensin administration. Life Sci , Res , 55 (2000) 72. 22 (1978) 1043. 43 Yamada M, yamada M, Watson MA & Richelson E, 27 Gui X & Carraway RE, Enhancement of jejunal absorption Deletion mutation in the putative third intracellular loop of of conjugated bile acid by Neurotensin in rats. the rat Neurotensin receptor abolishes PI hydrolysis but not Gastroentrology , 120 (2001) 151. cAMP formation in CHO-K1 cells. Mol Pharmacol , 46 28 Fujimura MT, Sakamoto T, Khalil T, Greeley G, Townsend (1994) 470. C & Thomspson J, Physiological role of Neurotensin in gall 44 Quirion R, Rowe B, Lapchak PA, Aravajo DM & Beaudet A, bladder contraction in dog. Surg Forum , 35 (1994) 192. Distribution of Neurotensin receptors in mammalian brain. 29 Gui X, Degolier TF, Duke GE & Carraway RE, Neurotensin Ann N Y Acad Sci , 668 (1992) 109. elevates hepatic bile acid secretion in chickens by a 45 Kitabgi P, Nadai FD, Rovere C & Bidard JN, Biosynthesis, mechanism requiring an intact enterohepatic circulation. release and degradation of Neurotensin and Neuromedin N. Comp Biochem Physiol C , 127 (2000) 61. Ann N Y Acad Sci , 668 (1992) 30. 30 Hammer RA, Carraway RE & Leeman SE, Elevation of 46 Aronin N, Carraway RE, Ferris C, Hammer RA & Leeman plasma Neurotensin – like immunereactivity after meal. SE, The stability and metabolism of Neurotensin in sheep. J Clin Invest , 70 (1982) 74. Peptides , 3 (1982) 637. 31 Degolier TF, Place AR, Duke GE & Carraway RE, 47 Shulkes A, Fletcher DR & Hardy KJ, Organ and plasma metabolism Neurotensin modulates the composition of pancreatic of Neurotensin in sheep. Am J Physiol , 245 (1983) E457. exocrine secretion in chicken. J Exp Zool , 283 (1999) 455. 48 Kitabgi P, Functional domains of the subtype1 Neurotensin 32 Andersson S, Rosell S, Hjelenquist U, Chang D & Folkers K, receptors (NTS1). Peptides , 27 (2006) 2461. Inhibition of gastric and intestinal motor activity in dogs by 49 Pelaprat D, Interactions between Neurotensin receptors and Neurotensin. Acta Physiol Scand , 100 (1977) 231. G proteins. Peptides , 27 (2006) 2476. 33 Sundler F, Hakanson R, Hammer RA, Carraway RE, Leeman 50 Devadar C, Beraud-Dufour S, Coppola T & Mazella J, The SE & Zimmerman E, Immunohistochemical localization of anti-apoptotic role of Neurotensin. Cell , 2 (2013) 124. Neurotensin in endocrine cells of the gut. Cell Tissue Res , 51 Boules M, Li Z, Smith K, Fredrikson P & Richelson E, 178 (1977) 313. Diverse roles of Neurotensin agonists in the central nervous 34 Melander O, Maisel AS, Almgren P, Belting M, Hedblad B, system. Front Endocrinol , 4 (2013) 1. Engstrom G, Kilger U, Nilsson P, Bergmann A & Orho- 52 Bozzola M, Ntodou-Thome A, Bona G, Autelli M, Magnani Melander M. Plasma pro – Neurotensin and incidence of ML & Radetti G & Schimpff RM, Possible role of plasma diabetes, cardiovascular disease, breast cancer and mortality. Neurotensin on Growth Hormone regulation in neonates. J J Am Med Asso , 308 (2012) 1469. Pediatr Endocrinol Metab , 11 (1998) 607. 35 Jing Li, Jun S, Zaytseva YY, Yajuan L, Piotr R, Kai J, Marlene 53 Pan JT, Tian Y, Lookingland KJ & Moore KE, Neurotensin E, Tae KJ, Harris JW, Frederique BY. Katz WS, Nilsson PM, induced activation of hypothalamic dopaminergic neurons is Orho-Melander M, Chen J; Haining Z, Fahrenholz T, Higashi, accompanied by a decrease in pituitary secretion of prolactin and RM, Gao T; Morris AJ, Cassis LA, Fan TWM, Weiss, HL, α – Melanocyte stimulating hormone. Life Sci , 50 (1992) 2011. Dobner PR, Melander O, Jia J & Evers MB, An obligatory role 54 Stolakis V, Kalafatakis K, Botis J, Zarros A& Liapi C, The of Neurotensin in high-fat diet-induced obesity. Nature , 533 regulatory role of Neurotensin on the hypothalamic – anterior (2016) 411. pituitary axons: emphasis on the control of thyroid related 36 Feurle GE, Muller B & Rix E, Neurotensin induces functions. Neuropeptides , 44 (2010) 1. hyperplasia of the pancreas and growth of the gastric antrum 55 Boules M, Cusack B, Zhao L, Fauq A, McCormick DJ & in rats. Gut , 28(1987)19. Richelson E, A novel Neurotensin peptide analog given 37 Assimakopoulos SF, Chrisoula DS, Nikolopoulou VN & extra-cranially decreases food intake and weight in rodents. Vagianos CE, Pleiotropic effects of Bombesin and Brain Res , 865 (2000) 35. MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES 21
56 Vincent JP, Neurotensin receptors, binding properties, 74 Vita N, Oury-Donut F, Chalon P, Guillemot M, Kaghad M, transduction mechanisms and purifications. Ann N Y Acad Bachy A, Thurneyssen O, Garcia S, Poinot-Chazel C, Sci , 668 (1992) 90. Casellars P, Keane P, Le Fur G, Maffrand J P, Soubrie P, 57 Tanaka K, Masuo M & Nakanishi S, Structure and functional Caput D & Ferrara P, Eur J Pharmacol, 360 (1998) 265. expression of the cloned rat Neurotensin receptor. Neuron, 4 75 Peterson C M, Nielson M S, Jacobsen C, Tauris J, Jacobsen (1990) 847. L, Gliemann J, Moestrup SK & Madsen P, EMBO J , 58 Mendez M, Souaze F, Nagano M, Kelly PA, Rostene W & 18 (1999) 595. Forgez P, High affinity Neurotensin receptor mRNA 76 Farra CD, Philippe S, Navarro V, Botto JM, Mazella J & distribution in rat brain and peripheral tissues. J Mol Vincent JP, Involvement of Neurotensin receptor subtype Neurosci , 9 (1997) 93. NTR3 in the growth effect of Neurotensin on cancer cell 59 Cochrane DE, Carrawy RE, Harrington K, Laudon M, lines. Int J Cancer , 92 (2001) 503. Rawlings S & Feldberg R S, HMC-1, human mast cells 77 Geisler S, Berod A, Zahm DS & Rostene W, Brain synthesize, Neurotensin precursors, secrete bio-active NT- Neurotensin, psychostimulants and stress emphasis on like peptides and express Neurotensin receptor NTS-1. neuroanatomic substrates. Peptides , 27 (2006) 2264. Inflamm Res , 60 (2011), 1139. 78 Martin S, Navarro V, Vincent J P & Mazella J, Neurotensin 60 Mazella J, Zsurger N, Navarro V, Chabry J, Kaghdad M, receptor – 1 and -3 complex modulates the cellular signaling Caput D, Ferraa P, Vita N, Gully D, Maffrand JP & Vincent of Neurotensin in the HT29 cell line. Gastroenterology , 123 JP, The 100-kDa Neurotensin Receptor Is gp95/Sortilin, A (2002) 1135. Non-G-Protein-coupled Receptor. J Biol Chem , 273 79 Ferraro L, Beggiato S, Tomasini M C, Antonelli T, (1998) 26273. Tanganelli S & Fuxe K, Neurotensin NTS1-Dopamine D2 61 Mazella J, Sortilin / Neurotensin receptor – 3: A novel tool to receptor – receptor interactions in putative receptor investigate Neurotensin signaling and cellular trafficking. heteromers: relevance for Schizophrenia. Austin J Psychiatry Cell Signal , 13 (2001)1. Behav Sci , 1 (2014) 2. 62 Gene bank data – www.ncbi.nlm.nih.gov/gene. 80 Dobner P R, Multitasking with Neurotensin in the central 63 Strange PG, Agonist binding, agonist affinity and agonist nervous system. Cell Mol Life Sci , 62 (2005) 1946. efficacy at G protein-coupled receptors. Brit J Pharmacol , 81 Dobner PR, Deutch AY & Fadel J, Dual role in 153 (2008) 1353. psychostimulant and antipsychotic drug responses. Life Sci , 64 Mitra SP, Muraki K, Brown DR, Parsons AM & Carraway 73 (2003) 801. RE, Canine Neurotensin, Neurotensin 6-13 , Neuromedin N: 82 Burgevin MC, Castel MN, Quarteronet D, Chevet D & Primary structure and receptor activity. Reg Peptide , 28 Laudron PM, Neurotensin increases tyrosine hydroxylase (1990) 11. mRNA-positive neurons in substantia niagra after retrograde 65 Mitra SP & Carraway RE, Chicken liver contains large axonal transport. Neurosci , 49 (1992) 627. quantity of G protein linked Neurotensin receptor. Peptides , 83 Fuxe K, Agnati LF, von-Euler G, Tanganelli S, O’Connor 16 (1995) 471. WT, Ferre S, Hedlund P &Zoli M, Neuropeptides, excitatory 125 66 Mitra SP & Carraway RE, High affinity binding of I-NT to aminoacids and adenosine A 2 receptors regulate D 2 receptors dispersed cells from chicken liver and brain. Peptides , 18, via intramembrane receptor-receptor interactions for 1997, 521. Parkinson’s disease and Schizophrenia. Neurochem Int , 20 67 Mitra SP, Carraway RE, Blute R Jr & Luber-Narod J, (1992) 2155. Agonist induced conformation alteration of Neurotensin 84 Binder EB, Kinkead B, Owens MJ & Nemeroff CB, receptor and mechanism behind Na + inhibition of 125 I-NT Neurotensin and dopamine interactions. Pharmacol Rev , binding. J Recep Signal Trans Res , 19 (1999) 995. 53 (2001) 453. 68 Carraway RE & Mitra SP, Implication of two receptor 85 Kinkead B & Nemeroff CB, Neurotensin, Schizophrenia and subtypes, one releasing acetylcholine and one Substance P, anti-psychotic drug actions. Int Rev Neurobiol , 59 which mediate contractile effect of Neurotensin in guineapig (2004) 327. ileum. Reg Peptide , 40 (1992) 120. 86 Kalivas PW & Duffy P, Effect of acute and daily Neurotensin 69 Mitra SP & Carraway RE, Importance of thiol group(s) in the and Enkephalin treatments on extracellular dopamine in the binding of 125 I-labeled Neurotensin from porcine brain. nucleus accumbens. J Neurosci , 10 (1990) 2940. Peptides , 14 (1993) 185. 87 Kalivas PW, Blockade of Neurotensin induced motor activity 70 Najimi M, Gailly P, Maloteaux JM & Hermans E, Distinct by inhibition of protein kinase. Psychopharmacol , 114 regions of the high affinity Neurotensin receptor mediates the (1994) 175. functional coupling with pertussis toxin sensitive and 88 Richelson E, Boules M & Fredrickson P, Neurotensin insensitive G proteins. FEBS Lett , 512 (2002) 329. agonists: possible drugs for treatment of psychostimulant 71 Mazella J & Vincent JP, Functional roles of NTS2 and NTS3 abuse. Life Sci, 73 (2003) 679. receptors. Peptides , 27 (2006), 2469. 89 Ferraro L, Antonelli T, Beggiato S, Christina – Tomasini M, 72 Martin S, Botto JM, Vincent JP & Mazella J, Pivotal role of an Stearodo A, Fuxe K & Tanagnelli S, Mecahnisms in Parkinson’s aspartate residue in Na + sensitivity and coupling to G proteins of Disease In Models and treatments (Ed Dushanova J, INTECH Neurotensin receptors. Mol Pharmacol , 55 (1999) 210. Europe, Slavka Krautzeka 83/A, 51000 Rijeka, Croatia) 2002. 73 Richard F, Barroso S, Martinez J, Labbe-Jullie C & Kitabgi 90 Schimff RM, Avard C, Fenlon G, Lhiaubet AM, Tenneze L, P, Agonism, inverse agonism and neutral agonism at the Vidailhet M & Rostene W, Increased plasma Neurotensin constitutively active Neurotensin receptor 2. Mol Pharmacol , concentrations in patients with Parkinson’s Disease. J Neurol 60 (2001) 1392. Neurosurg Psychiatr , 70 (2001) 784. 22 INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017
91 Fernandez A, Jenner P, Marsden CD & De Ceballos ML, apoptosis via activation of a receptor complex of p75NTR Characterization of Neurotensin like immunereactivity in and Sortilin. J Neurosci , 25 (2005) 5455. substantianigra in Parkinson’s disease. Peptides , 16 (1995) 108 Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen 339. MS Jacobsen C, Kleimannel M, Schwarz E, Willnow TE, 92 Yamada M & Richelson E, Heterogeneity of melanized Hempstead BL & Petersen CM, Sortilin is essential for pro- neurons expressing Neurotensin receptor mRNA in the NGF induced neuronal cell death. Nature , 427 (2004) 843. substantianigra and nucleus paranigralis of control and 109 Emmett MR, Andren PE & Capriol RM, Specific molecular Parkinson’s disease brain. Neurosci , 64 (1995) 405. mass detection of endogenously released neuropeptides using 93 Caceda R, Kinkead B & Nemeroff CB, Neurotensin: Role in in vivo microdialysis / mass spectrometry. J Neurosci psychiatric and neurological diseases. Peptides , 27 (2006) 2385. Methods , 62 (1995) 141. 94 Jolicieur FB, Rivest R, St-Pierre S & Drumheller A, 110 Santos AM, Lopez- Sanchez N, Martin – Oliva D, de la Villa Antiparkinson like effects of Neurotensin in 6 – Hydroxy P, Cuadros MA & Frade JM, Sortilin participates in light- dopamine lesioned rats. Brain Res , 538 (1991) 187. dependent photoreceptor degeneration in vivo. PLOS One , 95 Boules M, Warrington L, Fauq A, McCormick D & 7 (2012) 336243. Richelson E, Antiparkinson like effects of a novel 111 Bourcier T, Ronden N, Paquent S, Forgez P, Lombet A, Neurotensin analog in unilaterally 6 – Hydroxy dopamine Pouzaud F, Rostene W, Borderie V, & Laroche L, lesioned rats. Eur J Pharmacol , 428 (2001) 227. Expression of Neurotensin receptors in human corneal 96 Burns A& Iliffe S, Alzheimer’s disease. Brit Med J , 338 keratocytes. Invest Opthal Vis Sci , 43 (2002) 1765. (2009) b158. 112 Nemeroff CB, Osbahr AJ, Maniberg PJ, Ervin GN & Prange 97 Pohanka M, Cholinesterases, a target of pharmacology and A , Alteration in nociception and body temperature after toxicology. Biomed Pap Med FacUniv Palacky Olmouc intercisternal administration of Neurotensin, β – endorphin, Czech Repub , 155 (2011) 219. other endogenous peptides and Morphine. Proc Natl Acad 98 Birks J & Harvey RJ, Donepezil for dementia due to Sci (USA) , 76 (1979) 5368. Alzheimer’s disease. Cochrane Database Syst Rev , 25 (2006) 113 Al – Rodhan NR, Richelson E, Gilbert JA, McCormick DJ, CD001190. Kanba KS, Pfenning MA, Nelson A, Larson EW & Yaksh T 99 Lipton SA, Paradigm shift in neuroprotection by NMDA L, Structure activity of Neurotensin and some analogues in receptor blockade: Memantine and beyond. Nature Rev Drug the periaqueductal grey region of the brain stem. Brain Res , Discov , 5 (2006) 160. 557 (1991) 227. 100 Raino P, Santaguida P, Ismaila A, Patterson C, Cowan D, 114 Fang FG, Moreau JL & Fields HL, Dose-dependent anti- Levine M, Booker L & Oremus M, Effectiveness of nociceptive action of Neurotensin microinjected into the Cholinesterase inhibitors and memantine for treating rostroventromedial medulla of the rat. Brain Res , dementia: evidence review for a clinical practice guide line. 420 (1987) 171. Anal Int Med , 148 (2008) 379. 115 Urban MO & Smith DJ, Role of Neurotensin in the nucleus 101 Xiao Z, Cliz N, Kurada L, Hu B, Yang C, Wada E & Combs raphe magnus in opoid-induced anti-nociception from CK, Porter JE, Lesage F & Lei S, Activation of Neurotensin periaqueductal grey. J Pharmacol Exp Ther , 265 (1993) 580. receptor-1 facilitates neuronal excitability and spatial learning 116 Smith DJ, Hawranko AA, Monroe PJ, Gully D, Urban D, and memory in the entorhinal cortex: beneficial actions in Urban MO & Craig CR, Smith JP & Smith DL, Dose- Alzheimer’s disease model. J Neurosci , 34 (2014) 7027. dependent pain-facilitatory and inhibitory actions of 102 Hamid EH, Hyde TM, Egan MF, Wolf SS, Herman MM, Neurotensin are revealed by SR48692, a non-peptide Nemeroff CB & Kleiman JE, Neurotensin receptor binding Neurotensin antagonist: influence on the anti-nociceptive abnormalities in the entorhinal cortex in schizophrenia and effect of Morphine. J Pharmacol Exp Ther , 282 (1997) 899. affective disorders. Bio Psychitr , 51 (2002) 795. 117 Wu Z, Martinez-Fong D, Tre Daniel J & Forgez P, Neurotensin 103 Gahete MD, Rubio A, Cordoba-Chacon J, Garcia_navarro F, and its high affinity receptor-1 as a potential pharmacological Kinemam RD, Avila J, Castano JP, Expression of Ghrelin target in cancer therapy. Front Endocrinol , 3 (2013) 184. and Neurotensin systems is altered in the temporal lobe of 118 Somai S, Gompel A, Rostene W & Forgez P, Neurotensin Alzheimer’s patients. J Alzheimer Dis , 22 (2010) 819. counteracts apoptosis in breast cancer cell. Biochem Biophys 104 Jansen P, Gieh K, Nyengaard JR, Teng K, Lioubinski O, Res Commun , 295 (2002) 482. Sjoegaard SS, Breidehoff T, Gotthardt M, Lin F, Eilers A, 119 Martin S, Navarro V, Vincent JP & Mazella J, Neurotensin Petersen CM, Lewin GR, Hempstead BL, Willow TE & receptor – 1 and – 3 complex modulates the cellular signaling Nykjaer A, Roles of pro-neurotrophin receptor Sortilin in of Neurotensin in the HT-29 cell line. Gastroenterol , 123 neural development, aging and brain injury. Nat Neurosci , 10 (2002) 1135. (2007) 1449. 120 Dal-Farra C, Sarret P, Navarro V, Botto JM, Mazella J & 105 Brennan C, Rivas-Plata K & Landis SC, The p75 Vincent JP, Involvement of the Neurotensin receptor subtype neurotrophin receptor influences NT-3 responsiveness of NTR-3 in the growth effect of the Neurotensin on cancer cell sympathetic neurons in vivo. Nat Neurosci , 2 (1999) 699. lines. Int J Cancer , 92 (2001) 503. 106 Nykjaer A& Willnow TE, Sortilin: A receptor to regulate 121 Davis TP, Burgess HS, Crowell S, Moody TW, Culling- neuronal viability and function. Trends Neurosci , 35 (2012) Berglund A& Liu R H, β – endorphin and Neurotensin stimulate 270. in vitro clonal growth of human SCLC cells. Eur J Pharmacol , 107 Teng HK, Teng KK, Lee R, Wright S, Trevar S, Almeida 161 (1989) 283. RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, 122 Yamada M, Ohata H, Momose K, Yamada M & Richelson E, Nykjaer A & Hempstead BL, Pro-BDNF induces neuronal Pharmacological characterization of SR48692 sensitive MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES 23
Neurotensin receptor in human pancreatic cancer cells, MIA- 131 Bredeloux P, Cavalier F, Dubuc I, Vivet B, Costentin J & PaCa-2. Res Commun Mol Pathol Pharamcol , 90 (1995) 37. Martinez J, Synthesis and biological effects of c(Lys-Lys- 123 Souazae F, Dupouy S, Viardot-Foucault V, Bruyneel E, Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012), a Attoub S, Gespoch C, Gompel A & Forgez P, Expression of new analogue of neurotensin that crosses the blood-brain Neurotensin and NT-1 receptor in human breast cancer: A barrier. J Med Chem , 51 (2008) 1610. potential role in tumor progression. Cancer Res , 66 132 Bracci L, Falciani C, Lelli B, Lozzi L, Runci Y. Pini A, (2006) 6243. Grazilla De Montis M, Tagliamonte A & Neri P, Synthetic 124 Giorgio RR, Chile T, Bello AR, Reys R, Fortes MAHZ, peptides in the form of dendrimers become resistant to Machado MC, Cescato VA, Muslimo NR, Bronstein MD, protease activity. J Biol Chem , 278 (2003) 46590. Giannella-Neto D & Correa-Giannella ML, Expression of 133 Garcia-Garayoa E, Blauenstein P, Blanc A, Maes V, Touwe Neurotensin and its receptors in pituitary adenomas. D & Schubiger PA, A stable Neurotensin-based radio- J Neuroendocrinol , 20 (2008) 1052. pharmaceuticals for targeted imaging and therapy of 125 Myers RM, Shearman JW, Kitching OM, Ramos-Montoya Neurotensin receptor-positive tumors. Eur J Nucl Med A, Neal DE & Ley SV, Cancer, chemistry and the cell: Imaging , 36 (2009) 37. Molecules that interact with Neurotensin receptors. ACS 134 Mitra SP, Lipid nano-particles in medicine: Production, Chem Biol 4, (2009) 503. stability and drug-delivery. J Surf Sci Technol , 27 (2011) 1.
126 Mitra SP & Carraway RE, Synergistic effects of Neurotensin 135 Snider RM, Pereira DA, Longo KP, Davidson RE, Vinick FJ, and β – adrenergic agonist on 3’, 5’- cyclic adenosine Laitinen K, Gene-Schitoglu E & Crawley JN, UK-73093: A monophosphate accumulation and DNA synthesis in prostate non-peptide Neurotensin receptor antagonist. Bioorg Med cancer cells. Biochem Pharmacol , 57 (1999) 1391. Chem Lett , 2 (1992) 1535. 127 Mitra SP, Cell surface binding, intracellular cAMP elevation 136 Chakravarty PK, Chen A, Naylor EM, Ransom RW, Schneck and membrane associated G-protein activation by ( R,R-) and KA & Clineschmidt BV, Phalazinone biphenyl (S,S-) Formoterols in androgen independent human prostate acylsulphonamides: A new class of non-peptide Neurotensin cancer cell line, PC3. J Surf Sci Technol , 24 (2008) 87. antagonists. In: Proceedings of the 206 th ACS National 128 Carraway RE & Mitra SP, Neurotensin enhances agonist meeting Chicago, IL, PMEDI, ACS, Aug 22-27 Washington induced cAMP accumulation in PC3 cells via Ca +2 – dependent DC 1993. adenylyl cyclase. Mol Cell Endocrinol , 144 (1998) 47. 129 Pederson JH, Beck H, Shokouh-Amiri M & Fischer E, Effect 137 Johnson SJ, Akunne HC, Heffner TG, Kesten SR, Pugsley of Neurotensin in the dumping syndrome. Scand J TA, Wise LD & Wustrow DJ, Novel small molecule Gastroenterol , 21 (1986) 478. Neurotensin antagonists: 3-(1,5-diaryl-1,5-dioxopentan-3-yl) 130 Shimizu S, Tsukada J, Sugimoto T, Kikkawa N, Sasaki K, benzoic acids. Biorg Med Chem Lett , 7 (1997) 561.
Chazono H, Hanazawa T, Okamoto Y & Seki N, Identification 138 Helynck G, Dubertrel C, Frechet D & Leboul J, Isolation of of novel therapeutic target for head and neck squamous cell RP66453, a new secondary peptide metabolite from carcinomas: a role of Neurotensin – Neurotensin receptor -1 Streptomyces sp useful for Neurotensin antagonists. oncogenic pathway. Int J Cancer , 123 (2008) 1816. J Antibiot , 51 (1998) 512.