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: [email protected] 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.
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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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