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, IP3, Neurotensin, Neurotensin receptor, pain, Parkinson’s disease, Schizophrenia, Sortilin

General features of Neurotensin: Multitude of information are collected on NT, a tri-

decapeptide (<pQLYENKPRRPYIL-CO2H) isolated

from the bovine hypothalamus and intestine1.The

peptide acts as a neuro-transmitter conducting inter-

cellular and inter-neuronal signal processing like the

previously known vaso-active amines (Serotonin,

Dopamine, Nor-epinephrine, Catecholamine, Histamine,

and Acetyl-choline, etc). Before the advent of NT and

other peptides, those amines are considered as being the

only neuronal signaling agents. Along with the

discovery of NT, a long array of neuro-peptides

appeared on the scene and later recognized to be in the

family of neurotransmitters. The sequential and

phylogenetic study revealed that NT is well conserved

within the most mammals like bovine, dog, rat, and

human. For non-mammalian species, some changes

have occurred as noticed in the case of chicken

(<pQLHVNKARRPYIL-CO2H)2,3

. The genetic

mapping finds the location of NT to be within a

chromosome, q12 for the human4. Incidentally, the NT

mRNA can be induced in the brain by caffeine,

Staurosporine, Sigma receptor antagonists or even by the

osmotic stimulation5,6

. Concerning its physical nature

according to AA sequence, the peptide is significantly

basic for holding - KXRR- (X = P/A) patch within the

mid-region. The structure factor analysis indicates that, -

RRPYIL-CO2H moiety (NT8-13

) is crucial forthe

receptor binding and exerting any biologic events7. Any

__________

*Correspondence:

Phone: 508-752-3554

E-mail: smitra3554@gmail.com Abbreviation: AA, Amino acid; AD, Alzheimer disease; CA,

Central amygdala; cAMP, Cyclic adenosine mono-phosphate;

CCK, Chole-cystokinin; cGMP, Cyclic guanosine mono-

phosphate; CNS, Central nervous system; CRH, Corticotropin

releasing hormone; CSF, Cerebo-spinal fluid; DA, Dopamine;

DTPA, Di-ethylene-tri-amine pentacetate; EC, Entorhinal cortex;

ER, Endo plasmic reticulum; GABA, Gamma amino butyric acid;

GC, Guanylate cyclase; GDP, Guanosine di-phosphate; GF,

Growth factor; GH, Growth hormone; GHRH, Growth hormone

releasing hormone; GI, Gastro intestine; GP, Globus palladus;

GPCR, G-protein coupled receptor; GTP, Guanosine tri-

phosphate; HC, Hippocampus; MPTP, 1-Methyl-4-phenyl-

1,2,3,6-tetrahydropyrolidone; MTX, Methotrexate; NA, Nucleous

accumben; NMDA, N-methyl D- aspartate; NMN, Neuromedin

N; NT, Neurotensin; NTR, Neurotensin receptor; PD, Perkinson’s

disease; PGA, Preaqueductal grey area; PI, Phosphoinostide; PRL,

Prolactin; PLC, Phospho lipase C; PP, Pro-peptide; PTx, Pertussis

toxin; RNAi, Inhibitory ribo-nucleic acid; RVM, Rostro

ventricular medulla; SCLC, Small cell lung carcinoma; SCLC,

Small cell lung carcinoma; SN, Substantia nigra; VTA, Ventral

tagamental area.

INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017

8

minor changes within that sequence even switching –

CO2H to –CONH2 at the terminal endorstereo-chemical

modification of any AA significantly alters the binding

affinity (Kd) and capacity (Bmax) affecting the nature and

intensity of physiologic actions7. The intact peptide

(NT1-13

) and several of itsmajor –CO2H terminal

metabolites

(-NT4-13

, -NT6-13

& -NT8-13

) are equipotent to exert any

receptor mediated events both centrally and peripherally

evoking endocrine and exocrine functions7. The cDNA

cloning reveals that NT precursor carries another neuro-

peptide, Neuromedin-N (NMN) within its sequence,

which bears a bit of similarity (-KIPYIL-CO2H) at the –

CO2H end8. As a result, NMN cross-reacts (~30 %) with

the NTR7. Studies indicate that the NT/NMN precursor

undergoes differential post-translational processing in

the CNS and intestinal tissues9. In brain or CNS, NT and

NMN are processed simultaneously and stored inside

the synaptic vesicles within synaptosomes whereas for

intestine, the precursor processes by releasing only the

NT molecule while creating a large fragment of 21 AA

bearing NMN sequence at the–CO2H end9-11

(Fig. 1).

Often the processing event is seen different also for

the endocrine tumors where NT precursor is

processed by releasing numerous metabolites along

with the NT and NMN12

.

General role of NT: Initially, several physiologic

properties of NT are acknowledged through the

exogenous central administration, letting to

hypothesize its ability to induce narcolepsy,

hypothermia and analgesia5. Aside those effects, NT’s

role in behavioral aspects are also noteworthy. The

peptide induces anorexia and at a time increases the

water intake capacity5,13

. It enhances the sleeping time

when animals are particularly anesthetized by the

barbiturate or ethanol5. The incidence of low levels of

NT in CSF of schizophrenic patients compared to any

normal subjects shows that the peptide might have a

modulatory role in that disorder14,15

. As per its

peripheral actions, if injected intravenously, NT

lowers the blood pressure, induces bradycardia,

causes vaso-dilation and provokes cyanosis in

pento-barbital anesthetized Sprague-Dawly rats. The

massive release of Histamine has been implicated in

most of these incidents1, 5, 16

.

Inside the brain or CNS, NT’s existence is detected

at high level within anterior pituitary and

hypothalamus (Table 1).The peptide is storedin places

like NA and VTA along with the DA neurons within

mid brain also sometimes coexists with CCK5,16,17

. It

is also found in the brain stem and spinal neurons18,19

.

Regarding neuro-endocrine behavior, it enhances the

release of GF and PL20

. In mice brain, there is a rise

of NT mRNA expression during the postpartum

period21

. Further, the peptide increases ACTH level

with simultaneous enhancement of glucose and

cortisol in the serum22

. But it also lowers the level of

TSH, LH and thyroid hormone, T4. The effect is

thought to occur possibly for its effect on

hypothalamic TRH and ACTH23-26

.

As per gastrointestinal (GI) effect, NT allows contraction of the intestine, gall bladder, colon and pancreas

27-32. Its level (~10 pMol/L) rises (≥ 100

pMol/L) in the circulation after ingesting a fatty meal. The release is seen higher in case of unsaturated fatty acids (linoleic, oleic) compared to its saturated analogs

39. The release occurs mostly from the GI

mucosal cells30

. The released NT in circulation helps digestion by contracting the gall bladder enhancing the bile flow to saponify lipoid matter in food

28-31.

Alongside, while contracting the pancreas it delivers –HCO3 and lipase into the intestine to hydrolyze fats for easy and rapid absorption in the liver

31,32.

Additionally, the peptide also creates uneasy gastric reflux by relaxing the sphincter of esophagus

32. The

intestinal NT content follows an order of: Ileum ≥ Jejunum > Duodenum. The cells having NT are 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

illeal region33

. 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, diabetes or obesity

35.Using NT gene lacking mice

they have confirmed that the peptide enhances fat absorption both in vivo and in vitro via NTR-1 and NTR-3 leading to insulin resistance diabetes including obesity. The incidences of malignancies like, prostate, colon or breasts are also noticed since NT enables to induce the growth effect. It has been already documented that NT provokes atrophy of the intestine and stomach

36,37. In many endocrine tumors the higher

expression level of NT and NTR followed by its spontaneous secretion is seen to accelerate the malignancies via autocrine or paracrine pathway

38,39.

But as a normal behavior, NT’s release after meal is necessary to modulate the gastric motility which perhaps helps maintain a healthy bowl. Except in the case of incidental appearance of an abnormal phenotype, it may induce tumorigenicity which can be perpetuated later by its further release from the tumor tissues. The growth effect is confirmed in several endocrine tumors like prostate, colon, breasts, lung and pancreas. In all the cases, NT and its active fragments (-NT

4-13, -NT

6-13 or -NT

8-13) promote the

growth in both cultured cells and implanted tumors inside the nude mice

38-41. As for further validation, NT

is seen to induce the DNA synthesis in CHO cells expressing the NTR which is blocked by specific

NTR-1 antagonist, SR4869242,43

. In addition to those roles, more diverse and

complex role of NT is noted in the CNS. It is

observed to be heterogeneously distributed throughout

the CNS tissues18,44

. The levels are high within

hypothalamus, SN, VTA, CA, HC, NA, GP and

septum. Due to its potent neuro-modulatory role, NT

regulates many neuro-transmitting systems that are

dopaminergic, serotonergic, cholinergic, glutaminergic

or GABAergic by nature. By virtue of this nature, it

imposes number of behavioral and electrophysiological

effects to a different extent through the Na+ and Ca

+2

dependent releases44

.

Metabolism of NT: In circulating plasma, the

free/released NT lasts ~1.4 min before being degraded

by the endo- or exo-peptidases45

. The cleaving sites

are identified to be between Arg8–Arg

9, Pro

10–Tyr

11,

Tyr11

–Ile12

or Ile–Leu. The released metabolites are

inactive –NH2 terminal residues44

(Fig. 2).

Experiments made by steady infusion in aorta (200

pmol/Kg/hr) for ~1 h period shows that among all the

organs, kidney, intestine, liver and brain are majorly

responsible for the disappearance of NT1-13

or any of

its active –CO2H terminal metabolites46

.Out of them,

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+

Fig. 2—The major cleaving sites for NT and NMN during

enzymatic metabolism by endo and amino-peptidases.

INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017

10

kidney is seen to be heavily involved in the clearing

of both basal and stimulated version of NT. Several

experiments regarding its metabolism indicate that

NT can act as a local hormone working via autocrine

or paracrine pathway47

.

Physiologic role of NTRs: So far three different

receptors of NT have been identified that are widely

distributed throughout the body. A large number of

them are located inside the brain/CNS tissues or

spread along the digestive tracts or GI tracts. Among

those receptors, the NTR-1 is associated with major

physiologic effects regulating neurological, growth or

any endocrine actions16,48

. 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 act16,49

. 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 hypothermia5. Besides the

original peptide, several NT agonists are also

effective in inducing hypothermia or potentiating the

action of narcosis. But in all the cases, anti-

cholinergic, anti-serotonergic or anti-noradrenergic

drugs have failed to alter the effects5. 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 Prolactin5,51-55

.

General features of the NT receptors: The NTR was

detected at first by high affinity125

I–NT binding using

the brain plasma membranes from various

mammalian and non-mammalian tissues and later

confirmed by the cDNA cloning and sequencing56,57

.

Besides the CNS, NTR was identified in other organs

like liver, intestine, lung, kidneys and gall bladder

including the mast cells and several circulating

immune cells7,58,59

. The three types of NTR (NTR–1,

NTR–2 & NTR–3) are seen responsible for central,

peripheral or any other physiologic actions48,49,60

(Fig–3). Besides the differences in sizes and AA

sequences, those receptors bear vast dissimilarities

regarding structures and ligand binding characteristics

Fig. 3—Neurotensin receptors. A) NTR-1 showing 7TM (T1 to

T7) within the lipid bilayer. The agonist, NT8-13 binding domain

primarily comprises of T6, E3, and T7. The antagonist SR48692

blocks the space close to outside the cell surface within the turn of

T4, T6, and T7.)

Fig. 3 B—Neurotensin receptors shows several differences

between NTR-1 and NTR-2 concerning their ligand binding sites.

SR48692 acts as an agonist whereas NT behaves opposite, an

antagonist to the NTR-2. (The picture is redrawn by modifying

the publication of Vincent JP et al. Trends. Pharm. Sci.1999, Vol.

20. P302 -309)

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which is also reflected in their pharmacological

actions. As per similarity, both NTR-1 and NTR-2

belong to the GPCR super family, having usual seven

trans-membrane (7TM) strands spanning the cell

surface lipid bi-layer with –NH2 terminal exposing

outside and –CO2H end is dipping inside the cytosol

(Fig. 3A & B)49,60,61

. In human, the NTR-1and NTR- 2

genes are located respectively at chromosomes 20 and

2 whereas NTR-3 resides in the chromosome number

162

. Unlike others, NTR–3 is a straight chain poly-

peptide not belonging to the GPCR family having

single transmembrane whose–NH2 terminal protrudes

outside the cell surface and –CO2H terminal is

immersed inside the cytosol (Fig–3C). NTR - 3 is

identified to be a member of Sortilin family whose

ligand binding sites bear strong homology with the

protein gp 95/Sortilin that regulates intracellular

sorting and trafficking while influencing the cellular

growth and apoptosis60,61

. The observed AA sequence

indicates that NTR-1 (424 AA, ~48 KD) is about 10

AA larger than the NTR–2 (410 AA, ~45 KD)

whereas regarding molecular weight they appear to be

closer. NTR–2 bears ~64 % sequential homology with

the NTR–1 but both NTR-1 and –2 bears no

homology with NTR–3. It is seen somewhat bigger in

size having the molecular weight of ~95 KD (3A, B &

C). Concerning the physiological roles, they also act

differently48,49,56,57,60

.

NTR–1:Receptor characteristics and G-protein(s) association: It is the most common and widely studied NT

receptor. NTR–1 was identified and cloned

independently by many and from numerous sources.

The receptor displays high binding affinity

(Kd ~10–50 pM) toward 125

I-NT and evokes biologic

effects by activating versatile associated G- protein α–

subunits49,56,57

(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)

(Gαβγ) complex initiating a cascade of specific signaling

episodes allowing dissociate the GDP bound (Gα +

GDP) α subunit by exchanging with the cytosolic GTP

transforming to Gα + GTP complex. The incident

enables to activate series of enzymatic processes which

in essence direct the cellular behavior. In general, the

dissociation of α subunit from GDP by intracellular GTP

brings down affinity state (Kd) of the receptor thus

restricting the agonist binding ability. Experiments

conducted in its support using isolated plasma

membrane expressing NTR-1 proved the hypothesis.

The prior treatment with GTP or any non-hydrolysable

stable GTP analogs reduces the NT binding affinity (Kd)

and capacity (Bmax) significantly, a common feature that

is observed for all the GPCRs7,63-68

.

Concerning the ligand interactions, there are few

novelties associated with the NTR–1:

A) Promiscuity of NTR-1 attachment to the Gα

subunits

B) NT binding is susceptible to the Na+ ion and

C) Sensitivity toward the thiol (- SH) alkylating

agents that inhibit the NT interaction69

.

The compound SR48692 synthesized by Sanofi

Researchers acts as a specific antagonist that efficiently

inhibits the125

I-NT the binding (Ki~20 pM) and several

of its biologic and physiologic actions7,64-69

(Fig. 4).

Regarding the generation of second messengers, it is

recorded that NTenhances the intracellular ↑cAMP

level and often raises the cytosolic calcium (↑[Ca

+2]i)

also48,49

. Additional reports further indicate that in

certain neuronal cells it elicits the intracellular

↑cGMP level. The rise of intracellular ↑cGMP during

NT - NTR-1 interaction is often associated with the

prior formation of IP3 which in fact also helps elevate

the level of ↑[Ca

+2]i by releasing from the intracellular

store. In neuronal cells, especially in the case of

Dopaminergic neurons, initial rise of intracellular ↑[Ca

+2]i activates Nitric oxide synthase (NOS) leading

Fig. 3—Neurotensin receptors C) NTR-3. The receptor belongs to

the Sortilin family. About 5–10% of the total receptor is expressed

on the cell surface. It displays good affinity (Kd ~0.1-0.4 nM) after

the furin cleavage.

INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017

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to the generation of NO which in turn stimulates

Guanylate Cyclase (GC) enhancing the level of

↑cGMP. Uniquely, the NTR-1 is able to associate

with diverse Gα subunits via different intracellular

loops. As confirmed by the deletion and mutation

studies that, when NTR-1 is expressed in CHO-K1

cells, its third intracellular loop tends to associate with

the Gqα which takes part in the hydrolysis of phospho-

inositide (PI) through the activation of PLC producing

IP3 that subsequently releases Ca+2

from the

intracellular store of ER. Selective mutation of AA

within that loop wipes off that effect but retains the

↑cAMP elevating ability43,49

. Evidences indicate

further that often NTR-1 can associate with the PTx

sensitive, inhibitory Gαi. Treating with PTx causes

ribosylation of the Gαi, which afterward lowers the NT

binding and stimulated rise of cAMP70

. As a

distinctive feature, the multiple attachment of NTR-1

with different Gα subunits at a time is visible in many

instances49

.The reason remains unexplored. Needless

to say, a great many physiologic actions occur via this

receptor for its larger existence in both neuronal and

non-neuronal tissues.

NTR–2: Receptor’s actions and G-protein’s association: Compared to the type-1, NTR-2 displays lower

affinity (Kd ~10–100 nM) although both belong to the

GPCR family (Fig. 3B). The NT binding affinity is

seen even lower (Kd~10µM) in the case of rat brain.

The associated Gα with NTR-2 is identified as Gαq

which hydrolyzes PI during interaction with NT.

Unlike NTR-1, it is insensitive toward the Na+ ion

during 125

I-NT binding49,67,71-73

. It is proven that, the

presence of Asp at second intracellular loop makes

many GPCRs to be Na+ sensitive

72,73 (Fig. 3B).

Removing the Asp113

by neutral AA like Gly or Ala at

the second intracellular loop desensitizesNTR-1

toward the Na+ ion which is absent in the case of

NTR-272

. The NT binding with NTR-2 creates

phosphorylation of ErK1/2 due to the hydrolysis of PI

which causes internalization of the agonist bound

receptor as seen in rat brain49

. Interestingly in case of

NTR-2, the selective NTR-1 antagonist, SR48692

behaves as agonist elevating the ↑(Ca

+2)i which in a

surprising move is antagonized by the NT. It is

recorded that H1 antagonist, Levocabastine selectively

inhibits the 125

I-NT binding to NTR-2 (IC50 = 10.0

nM). The receptor is seen to be constitutively active

but NT has no role in this affair, instead, it

antagonizes the effect of agonists or inverse agonists

either fully or partially73,74

. The exact underlying

pharmacology is not known. Structurally, NTR-2

lacks N-glycosylation at the extracellular region

unlike its NTR-1counterpart74

(Fig. 3B).

NTR–3: Nature, location, and signaling: Distinctively,

NTR-3 is not exactly a cell surface receptor (Fig. 3C).

Only ~5–10 % of the total number of receptors

express extracellularly whereas the rests express

inside the cell61,75

. Attention is directed recently due

to its intimate involvement in the events of neuronal

functionality, mitogenicity and atrophy of the

organs61,76

. It is a single transmembrane glycoprotein

located mostly inside the ER of Golgi apparatus,

therefore, does not belong to the GPCR family. Its

actions are different by nature. It mainly participates

in course of intracellular trafficking61

. It is established

that during NT induced receptor internalization,

NTR-3 is pulled on the plasma membrane from its

internal sources. The event seems prominent for those

cells or neurons expressing the other NTRs since

other peptides fail in doing so77

. The agonist binding

affinity of NTR-3 is moderately high (Kd ~10-15 nM)

but when co-transfected with Furin and expressed in

COS-7 cells it shows a much high affinity

(Kd ~0.3 nM)75,76

. The receptor was detected by 125

I-

Fig. 4—The chemical structure of non-peptide NTR-1 antagonist SR 48692, UK-73093, PD156425, L-734836 and Levocbastine (H1

antagonist) that binds to NTR-2 and competes with the 125I- NT binding (IC50 ~10–50 nM). Levocabastine like NT can trigger the inward

current while interacting with the NTR-2 expressed in xenopous oocytes.

MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES

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NT binding and after isolating from the CHAPS

soluble human brain membrane using affinity

chromatography showing the Mw~100KD. Later it

has been cloned from the cDNA library of human

brain expressing 833 AA and displaying 100%

sequential homology with gp95/Sortilin particularly

after the Furin-cleaving site75

. Besides human, it is

also identified in mouse and rat brain neurons and is

seen to be responsible for the NT induced receptor

internalization60

. The studies demonstrated that

Sortilin/NTR-3 is synthesized as a precursor or pro-

protein which is afterward converted to the desired

form by Furin within the trans-Golgi network of ER.

The cleaving by Furin releases 44 AA pro-peptide

(PP) resulting in the creation of functional NTR-3.

Interestingly, this 44 AA PP efficiently resists the NT

binding therefore acts as a potent endogenous

inhibitor (Kd ~20–30 nM). If no cleaving occurs by

Furin to eliminate the PP then NT fails to bind that

precursor of NTR-3. It is thus hypothesized that this

44 AA PP when attached might impose a steric

hindrance while blocking the NT docking site75

.

The intracellular signallingvia NTR-3 is seemingly

more complex than the others since a scanty portions

(~5–10 %) are located on the cell surface but that

might be enough to influence the internalization of

NT bound NTRs61,75

. It has been noticed that in course

of NT induced internalization of receptor(s), a process

of hetero-dimerization occurs between NTR-1 and

NTR-3 which is a common incidence in many

carcinomas like in HT-29.The NT induced hetero-

dimer complex after internalization activates the MAP

kinase and hydrolyze PI which eventually results in

cell proliferation. The dimerization event does not

change the binding characteristics of NT to NTR-1.

At this situation, the ratio of NTR-1/NTR-3 is

approximately 1/10 to 1/20. Being alone NTR-3

cannot activate the MAP kinase or else hydrolyze the

PI. On the other hand its presence somehow decreases

the efficacy of NTR-1 to stimulate the MAPK or PI

hydrolysis78

. Like HT-29, a large section of epithelial

tumor cells belonging to lung, colon and prostate co-

express NTR-3 along with the NTR-1. Intuitively,

their dual and synchronized action during intracellular

signaling event exerts mitogenicity in vivo and in

vitro76

. Being alone NTR-3 only helps the normal

growth as seen for intestine76

. It could be a possibility

that NT binding and subsequent internalization of

NTR-3 might trigger the release of unknown trophic

factors that help express the normal growth. Studies

on cancer cell lines indicate that growth response by

NT requires mainly the NTR-3 but not NTR-1

although the antagonist SR48692 specific to NTR-1

inhibits the event76

. The incidence implicates a possibility

of the existence of another unidentified subtype of NTR.

Role of NT in neurological disorders

NT & NTR in schizophrenia and drug abuse :

Table 1 shows the presence of NT and NTRs in

some of the areas of mouse brain. It is proven that NT

often coexists withthe DA neurons within VTA or NA

or SN of hypothalamus5,17-19,44

. VTA expresses high

level of NTR and are heavily innervated with NT

containing neurons14

. The co-localization of NT in

DA neurons and its subsequent interactions after

release bear immense significance concerning the

schizophrenia and other psychotic disorders and also

simultaneous blocking of any hyperactivity produced

by the psycho-stimulants like amphetamine or

cocaine51,79-81

. Typically, greater than 80% of the DA

neurons express NTR-1 so the depolarization created

by NT may occur more frequently51,80

. Inside the NA,

NTR sits on both the pre and post-synaptic DA

receptors. At its pre-synaptic performance, NT blocks

the D2 auto-receptors by antagonizing the effect of

DA thereby enhancing its release thus increasing the

firings of the DA neurons while also raising the

additional intracellular Ca+2

level by interacting with

NTR-1. Due to this intimate connection between NT

and DA neurons and its subsequent neuro-regulatory

effect through their respective receptors, one can

speculate that NT or its agonists can be used as a

therapeutic measure in treating the schizophrenia

which is supported by the fact that central

administration of NT produces anti-psychotic effect51

.

Further, among the schizophrenics there is ~40%

decrease of NTR in the EC and the overall NT levels

are always low in their CSF15

. In drug free

schizophrenics also, the level of NT and its

metabolites are noticeably lower in CSF than any

normal subjects. Additionally, the levels also vary

with the severity of disease. Treatment with anti-

psychotic drugs often normalizes the levels in CSF15

.

It is thus envisaged that NT may act as a therapeutic

agent in treating this disorder since its central

administration induces anti-psychotic behavior15,51

.

The overall information so far indicates that DA

transmission is often modulated by the NT either

directly or indirectly: a) by up-regulating the tyrosine

hydroxylase (TH) mRNA in striatum thereby

INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017

14

enhancing the DA production or b) by lowering the

binding of DA to the D2 receptor which arises due to

steric interference created during simultaneous DA-D2

and NT-NTR interactions which also eventually

modifies the intracellular second messenger

generations82,84

. NTR’s existence is visualized in

those nerve terminals which deepens inside the cell

bodies and dendrites within SN and VTA44

. It is

mentionedalso that, NT opposes the DA effect in both

pre- and post-synaptic path ways, which either

enhances or lowers the DA regulated transmission

depending on locations inside the brain. But as a

whole, NT- NTR-1 interaction and DA release has a

positive effect toward the anti-psychotic disorder84,85

.

As a further addition, NT can act as a psycho-

stimulantalso which solely depends on the site of its

administration. If injected inside the VTA, NT or its

agonists act as a psycho stimulant increasing the

locomotor action because that area expresses high

extent of NTR. Since NT colocalizes with the DA

neurons so possibly rising DA level is thought to be

accountable for this event51,84-87

. The experiments

have proven this fact that if injected inside VTA, the

agonists enhance the hyperactivity by releasing DA

inside NA. On the contrary, when brain permeable

agonists (NT69L) are injected within the NA, it

lowers the responses of psycho-stimulants like D-

amphetamine or cocaine 86,87

. Therefore, endogenous

NT plays dual role acting as a natural psycho-

stimulant and also preventing the drug abuse. So,

stable and permeable NT agonists can be used for the

later event by preventing or weakening any behavioral

sensitization produced by the psycho-stimulants like

amphetamine or cocaine88

. Table 2 shows several

active analogs of NT having modified AA at different

positions of NT8-13

.

Role of NT and NTR in Parkinson’s disease (PD):

The exact role of NT in PD is hitherto

undetermined but studies convince its potential role

on this locomotor disorder. It is already

acknowledged that the peptide plays a significant role

regarding neuroplasticity and neurodegeneration

inside the basal ganglia. Importantly, it increases

glutamate induced excito-toxicity within the DA

neurons. In that way, NT-NTR-1 interaction

modulates the effect created during NMDA receptor

activation89

. So it is logical to assume that NTR-1

antagonists can be utilized in the course of PD therapy

which indeed shows a promising effect.

It is noticed that in most PD affected patients the

average NT level in plasma is ~2 fold higher than the

normal control subjects irrespective of the sexes90

. It

is also seen that NT immunoreactivity increases

within the SN of PD patients especially at zona

compacta and zona reticulata91

(~2 fold). Studies

indicate further that the lesser amount of DA neurons

and subsequent lesser expression of NTR-1 occur

within those areas for most PD patients92

.

Experiments on rats while inducing PD by applying

MPTP (Fig. 5) produces the similar results93

. As per

conclusion, there exists a definite correlation between

NT-NTR and DA-D2 interactions in the disease. The

lesser functionality of NTR-1 is seen to occur due to

neuronal degradation which arises during the

progression of PD. It could be a reason why the level

of NT immunoreactivity in those tissues is seen

higher which also reflects its higher level in the CSF

and plasma. It is hypothesized by Caceda et al. that it

is a part of compensatory mechanism why the NT

level is raised high because in that way motor

functions of the DA neurons are attempting to be

preserved93

. It could be also a possibility that

deregulations of neural transmission of NT may

follow the other striatopallidal pathway. Experiments

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

Fig. 5—The chemical conversion of MPTP (1-Methyl-4-phenyl-

1,2,3,6 tetra-hydro pyridine) to MPP+ (1-Methyl–4phenyl

pyridinium ion) by Mono-amine oxidase B (MAO-B). MPP+ is

toxic and creates Parkinson like syndrome by disrupting dopamine

producing neurons in SN. It inactivates the tyrosine hydroxylase.

MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES

15

using the neuro-toxin (6-hydroxy-dopamine) showed

that bilateral injection of NT in the medial forebrain

bundle attenuates the muscle rigidity and tremor94

.

Similar results are obtained using the NT agonist

(NT69L) during amphetamine or apomorphine

induced rotatory behavior95

. But despite that fact, the

role of NT enhancing the glutamate excito-toxicity in

DA neurons takes much precedence89

. So the use of

antagonists are thought to be a positive approach in

this concern.

Role of NT and NTR in Alzheimer Disease (AD):

Continuing decay of cognitive ability is the sole

sign of AD96

. Either to prevent the further decay or to

improve the detoriating cognitive function is a general

approach regarding the disease’s therapy. The current

treatments include choline esterase inhibitors

(Donepezil, Rivastigmine, Exelon or the natural

product Physostigmine) or partial antagonist of

Glutametargic NMDA receptor, Memantine97-99

(Fig. 6). But the success is so far limited and lasts

only for a brief period of time. Additionally, the

response largely relies on a small group of patients

but not for all100

. It is noticed that NT and NTR

containing fibres are densely populated within EC of

the brain. This area is important for exhibiting

learning and memory101

. At the onset of AD it shows

some structural perturbations which is signified as

being the pathological evidence102

. Studies at past

indicate that NT modulates cognition but the

mechanism stays unclear. According to the recent

studies, NT-NTR-1 interaction increases firing

frequency of the action potential which is afterward

mediated by the down-regulation of TREK-2 K+

channels. So, the micro-injection of permeable NT

agonist PD149163 (Fig. 7) inside EC enhances the

spatial learning behavior when assessed by using the

Barnes Maze Test101

. This agonist causes a persistent

increase in the firing frequency of action potential

which in turn helps the memory condition in APP/PSI

mice normally used as a model of AD. So NT and its

agonist exhibits beneficial role in the mouse model101

.

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 unchanged103

. 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

apoptosis104,105

. It is observed that neurotensinergic

system changes during aging or in any neuro-

degenerative diseases like AD. The mechanismis

unclear104

. Regarding biochemistry, it is established

that NTR-3/Sortilin can form heterodimer with the

neurotrophin receptors, eg, p75NTR, TrkA or TrkB to

trigger the cell death initiated by proNGF or

proBDNF106,107

. 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 5HT2Band 5HT2C serotonin receptors.

Fig.6—Chemical structure of several known drugs currently used

in the treatment of Alzheimer’s disease.

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16

blocked either by a high dose of NT (10 µM) or the

cleaved pro-domain peptide of pro-NGF (100µM)

which can antagonize while competing with the

binding site of NTR-3/Sortilin and pro-NGF108-110

.

Seemingly, the dose used for NT in the study shows

effectivity only at the higher concentration (10µM)

but its average level in the brain is ~50 pM110

. So the

controversy arises whether in reality NT actually

serves as a natural regulator. On the other hand, the

anti-apoptotic preventive role of NT has been

established by using the agonist JMV449 (1-10 nM)

while protecting the neurons like in the case of retinal

keratinocytes from illumination damage111

.From

overall perspectives, it is thus presumed that

endogenous NT could offer a protective role through

the anti-apoptotic behavior. Therefore in future, some

NT agonists can be used for the prevention of AD.

NT in pain & analgesia NT & NTR in pain and analgesia:Judging by the

dose-dependent anti-nociceptive action, NT or any of

its stable analogs appears to be more potent than the

morphine51,112,113

. If injected at nano-molar doses

inside the RVM, it shows a good anti-nociception

effect in response to the heat stimulus whereas, at

pico-molar doses it induces the opposite effect

facilitating spinal nociception reaction114,115

. The

dose-response curve indicates a possible role of two

different types of NT receptors or the involvement of

two separate and diverse neuronal pathways116

.

Uniquely, the anti-nociception effect induced by a

selective NTR-1 agonist, PD 149163 is partially

blocked by Yohimbine (α2 - adreno-receptor antagonist)

and also by the Serotonin blocker, Methyl Sergide

(5HT2B& 5HT2C serotonin receptors) (Fig. 7). On the

other hand anti-nociception produced by the NTR-2

agonist β–Lactotensin (-HIRL-CO2H) is blocked only

by the Yohimbine. So, the activation of NTR-1 in

RVM induces anti-nociception by releasing both nor-

epinephrine and serotonin from the spinal fibres

whereas the effect of NTR-2 is mediated only by the

nor-epinephrine release51

.

The overall anti-nociception action mediated via

NTRs also depends on the nature of tests and species

used during experiments. The involvement of NTR

regarding analgesia is surprisingly confusing51

.

Experiments conducted by using the NTR-1 gene

lacking mice or inhibiting it by introducing antisense

peptide nucleic acid proves hardly the role of NTR-1

in hot plate tests. But for same knockout mice, in

formalin induced persistent pain, NTR-1 is identified

to be the important pain modulator as seen during the

systemic administering of morphine51

. On the other

hand, NTR-2 is seen to be involved in agonist induced

analgesic effect both in thermal nociception and also

during the writhing tests118

. Introduction of

Levocabastine blocks that NT induced analgesic

effect whereas the NTR-1 antagonist SR48692 fails in

that performance identifying the specific involvement

of NTR-2 in this pain mediating event119

.

Interestingly, NT79 a selective NTR-2 agonist is

inactive in reducing the thermal pain but effective in

reducing acetic acid induced writhing tests in rats.

Whereas PD149163 a selective NTR-1 agonist and

nonselective agonist NT69L both can reduce the pain

level during inflammatory condition produced by the

formalin (Table. 2, Fig. 4). Those substances are also

effective in controlling the neuropathic pains120

. Studies

suggests that in near future, various NT analogs (Table. 2)

can be used in treating the various pain situations

(thermal, visceral and inflammatory conditions). But their

efficiencies would vary as per selectivity of the NTRs51

.

Role of NT in cancer NT & NTR in malignancy: The NT-NTR interaction

in the field of cancer draws serious attention in terms of

both cure and diagnosis. Numerous studies are on the

way for a proper understanding of intracellular pathways

involved in the biology of NT-NTR interactions relating

to malignancy117

. It is established that NT offers growth

to the normal and malignant cells both in vivo and in

vitro which is recorded for gastro-pancreatic cells,

prostate carcinomas, fibroblasts, hepatocytes, lung,

adrenal carcinomas, pituitary adenomas etc36-39,41

. In

most cases either the NTR-1 or NTR-3 individually or

dually participate in the growth promoting role. Some

studies insist that NT- NTR-1 interaction is primarily

involved in the act of malignant growth. But recent

works indicate that since NT prevents apoptosis via

NTR-3, so that may incite uncontrolled cell growth

encouraging the proliferation of cancer117,118

. The role of

NTR-3 has been studied in detail for breast cancer cell

line (MCF-7), colorectal carcinoma (HT29) and pituitary

adenomas111,117,119,124

. As one may hypothesize, that the

tissue specific expression of NT and NTRs offer a

balance of normalcy under a healthy condition which

becomes deregulated in the event of malignancy since

NTRs often over expressed in many aggressive tumors

derived from various sources like pancreas, prostate,

colon, lung, mammary glands etc38-41,119-124.

. Instances

emphasize that NT’s interaction with NTR-1 singularly

or jointly with NTR-3 is liable for the progression of

MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES

17

malignancies119,120

.

As a normal occurrence, human epithelial

mammary cells do not express NTR-1 but in the case

of carcinomas, like MCF-7, the over expression of

NTR-1 along with NT turns the growth uncontrolled.

The activation of Gαq during interaction leads to

activate the PLC and later Protein Kinase C (PKC)

which is known to enhance the tumor growth. It has

been demonstrated also that synthetic NT agonist

JMV449 (H-KΨ(CH2NH)-KPYIL-CO2H) helps the

cell-growth while inhibiting apoptosis via NTR-3 and

subsequently upregulating the expression of Bcl-2

without decreasing the p53 level118

. Besides the

growth effect, NT and its agonists assist the tumor

progression through metastasis, helping the malignant

cells to migrate for further invasion122

. Noticeably,

>90 % of the breast carcinoma expresses NTR-1. So,

depleting its expression either by treating with RNAi

or blocking the agonist’s interaction using SR48692

shows significant positive responses in reducing the

tumor progression124

. Similar effects are recorded in

the case of androgen independent human prostate

cancer cell lines, PC338,120

. Unlike the PC3, LNCaP

expresses both NTR-3 and NT.39,120

. These cells

undergo proliferation using own secretory NT

following autocrine pathway39,120

. But for the others,

cell growth may follow either endocrine or paracrine

path38,39

. In small cell lung carcinoma (SCLC), NT

offers growth possibly through the autocrine or

paracrine pathways since about 75% of human SCLC

cell lines express the NT mRNA125

. Besides the

SCLC, ~75% human non-SCLC cells also express

NTR-1 along with the NT132

. Experiments conducted

on tumor (human SCLC-NCl-H209) bearing nude

mice by orally administering the SR48692 caused

99% reduction of the tumor growth133

. Additionally,

SR48692 inhibits the NT induced growth of human

colon carcinoma (SW480) also. In this cells NT

enhances the size and tumor volume by >250 %134

.

The human pancreatic adenocarcinoma (90% of all

human pancreatic cancers having 5 year survival rate

of 3–5%) expresses NTR-1 which is noticeably absent

in the case of normal or tissues affected with chronic

pancreatitis. As for diagnosis, the appearance of NTR

is thought to be the initiation of pancreatic cancers135

.

The stimulation by NT induces mitogenicity in

MIAPaCa and PNC-1 cell lines derived from the

human pancreas expressing NTR-1121

. Although

direct involvement of NTR-1 is identified as being the

supreme cause but the role of NTR-3 is accounted

also, especially considering the results of in vitro

studies136

. Anyway, whichever pathways may be

followed, SR48692 can efficiently block the growth

in most situations. The works on pituitary cancer

indicate that in the case of functioning (hormone

secreting) pituitary adenoma the level of NT

expression is higher than the non-functioning or

normal pituitary gland. The NTR-3 is seen to be

expressed in both adenomas but not in the case of

normal pituitary tissue. Uniquely neither the NTR-1

nor NTR-2 mRNA is expressed in any adenomas or

normal pituitary gland. In this case NT may work via

autocrine/paracrine pathway during interacting only

with theNTR-3137

.

It has been established that NT alone enhances the

DNA synthesis in many tumor cell lines including

androgen independent PC338

. But uniquely, while

acting together with the β–agonist, Isoproterenol, NT

not only reverses the event and but also synergizes the

DNA lowering ability of isoproterenol

tremendously126

. In PC3, in addition to NTRs, β2–

adreno-receptor receptor is over expressed and β2–

agonists alone lower the DNA synthesis127

. But when

added with NT that lowering ability is highly

synergized in a dose-dependent manner128

. Other than

Isoproterenol, several β2-active anti-asthmatic drugs,

R-Albuterol or Formoterol (RR- or RS-) produces the

similar effect (Mitra SP, unpublished data). The

excessive rise of intracellular cAMP during co-

interaction is identified as being the leading cause

behind this non-proliferative effect126,128

.

Uses of NT and its analogs

The importance of NT- NTR interaction in health is

evidently wide. Thus attempts are made to use either

the NT or NTRs as a biomarker or for any other

therapeutic purposes. For that matter, several stable

analogs of NT, either the agonists or antagonists are

synthesized125

. The main obstacle to use NT as a

biomarker or therapeutic measure is due to its rapid

degradation within thecirculation (t1/2 ~2.3 min)129

.

But identifying NTR within an appropriate gland or

tissues which normally do not express can be utilized

for the cancer prognosis, especially for several

epithelial tumors125

.

It is noticed that agonism by NT displays beneficial

role on the psychotic disorders whereas antagonism is

indicative to the possible cure of tumor. Based on that

fact, few stable agonists and antagonists are

constructed to combat mental/neurological disorders

as also to cure the cancers. For example, the NTR-1

INDIAN J. BIOCHEM. BIOPHYS., VOL. 54, FEBRUARY–APRIL 2017

18

agonists (PD149163 & other non-peptide analogs) are

seen useful to treat the psychotic illnesses on the other

hand, antagonist, SR48692 displays anti-tumor

property51,88,117

(Table. 2, Fig. 4 & 7). Several

antagonists are on trial to be employed for treating the

cancers. In that regard, new antagonists belonging to

the category of peptidomimetics or cyclic-peptides, an

aromatic compound like RP66453 or a secondary

metabolite of macrocycle antibiotics Vancomycin

(from the Actinomycetes strain A9738) are

synthesized or isolated (Fig. 8). Concerning the

selectivity, later one binds to the guinea pig ileum

with high affinity (IC50 ~30µg/mL) expressing NTR-1

without interacting with NTR-2138

.

In addition to the medicinal uses, attempts are also

made to exploit the event of NT-NTR interaction for

molecular targeting125,130

. On that accord, toxic drugs

like Methotrexateor any imaging substances are

chemically conjugated to any stable NT analogs for

direct delivering to the tumor either for healing or

imaging purposes132,133

(Fig. 8). The process enhances

the bioavailability as well as permeability of the

conjugates allowing cross the blood-brain barrier.

Thus by creating a lipophilic magic bullet, it is

targeted directly to the diseased tissues

simultaneously avoiding any adversarial effects

toward the healthy organs125,134

.

To enhance the stability and enabling to cross the

CNS barrier, a modified lysine substituted cyclic NT

dipeptide (c<KKPYIL-KKPYIL>c) is now created by

chemically joining the NH2 terminal of lysine and

CO2H of leucine at the other end to use it as a stable

non-opioid analgesic131

. To achieve further an

extraordinary level of stability, dendrimeric peptide

analogs of NT are also created by covalently

conjugating at least four NT8-13

sequences (RRPYIL)

in certain ways which can be chemically linked to

many tumors destroying cytotoxic agents125,132

(Fig. 8). This dendrimeric peptide is stable in human

plasma for ~24 h at 37°C132

. If linked to the DTPA or

any other radio nuclides (111

In, 99m

Tc, 188

Re or 18

F)

then those probes could be used for both imaging and

therapeutic needs133

. It has been reported that the

covalently linked NT4 dendrimer with MTX can

reduce the tumor volume >60% while lowering the

side effect of MTX to a significant extent132

. As a

further strategy, often the peptides are also covalently

attached to the surface of lipid nano-carriers pre-

loaded with the toxic drugs inside. This also enhances

the bioavailability as well as the concentration of drug

regimens at the desired sites134

. Until now, majority of

the probes are made for targeting the NTR-1 but there

are others which can interact with the type-3 NTR

since in most carcinomas both receptors are often

expressed. The event of heterodimerization of

NTR-1 & 3 and subsequent internalization of the

agonist bound hetero dimer helps the process of

imaging and therapeutic ability.

Conclusion Besides acting as neuropeptide displaying

numerous neuronal effects, NT also influences effects

on a number of non-neuronal tissues. Those actions

insist to find many of its behavior, tissue specific

processing and biological uses. The current review

intends to highlight some of those facts about

NT- NTR interactions concerning health and diseases.

It is noticed that even after four decades of discovery

many of the features about NT remains un-identified

although significant progress is made to understand

Fig. 8—Chemical structure of new NTR-1 antagonist, RP66453 and NT4 conjugate, DTPA and Methotrexate.

MITRA: NEUROTENSIN & ITS RECEPTOR IN HEALTH AND DISEASES

19

some of its biochemical and patho-physiological

behavior. To better identify its role in normal and

diseased conditions, a number of NT mimetics are

constructed acting either as agonists or antagonists,

which are currently in the process of being used in

course of diagnosis or therapeutic needs. The peptide

is modified to ensure more stability, bioavailability

and also enabling it to cross the blood-brain barrier.

NT or any of its peptide - mimetics are introduced to

act as magic bullets for targeting the diseased organs

to deliver the toxic drug regimens. The selective

targeting would certainly lower the undesirable side

effects. Basing on that notion, several new drugs are

constructed to cure the schizophrenia, chronic pain,

alcoholism and others.

Aside its future uses, one biochemically

intriguing part is the differential processing nature

of NT precursor in neuronal and non-neuronal

tissues. Obviously, the event follows natural

demand. But the inherent cause behind this event

stays unexplained which may reveal many of the

unidentified physiologic roles played by NT.

Further the differential level of expression of

various NTRs in neuronal and non-neuronal tissues

is not thoroughly investigated. The downstream

signaling and subsequent feedback effects

involving other signaling molecules need further

study to offer more clarity to better understand

about the diseases and disorders. Additionally, the

exact role of NTR-2 is also not fully well

established.

Further, the importance of NTR-3 either alone or in

combination with others is not completely identified.

The uniqueness of NTR-3 belonging to the family of

Sortilin opens up a crucial chapter about the role of

NT in tumor progression and also the age related

neurological disorders like AD.

Acknowledgement The author gratefully acknowledges sincere help provided

by Dr Rajesh Kumar Barur, University Of Massachusetts

Medical School Worcester, during library work.

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