Neurotensin as a neuropeptide

1. NEUROTENSIN SYSTEM
Realised by :
 LGUENSAT Asmae
 OMARI Zineb
 BOUDJAFAD Zineb
Neuropharmacology
Pr. Philippe De Deurwaerdère

2. PLAN:
SYSTEM DESCRIPTION
NEUROTENSIN FUNCTIONS
DISEASE AND THERAPIES

3. I- SYSTEM DESCRIPTION

4. PRESENTATION OF NEUROTENSIN
 Endogenous peptide
Acts as neurotransmetter and neuromodulator in the
central nervous system.
Acts as hormone in the gastrointestinal tract.
 Made of 13 amino-acids (1674Da).
Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu
Majority of
pharmacological
properties

5. BIOSYNTHESIS
 Inactive precursor made of 120 amino acids called pro-neurotensin.
Neurotensin NT
Neuromedine NN

6. BIOSYNTHESIS
 The precursor is cleaved by the action of prohormone
convertase (PC).
Prohormones convertases
PC1 PC5-A PC2

7. STORAGE AND RELEASE
 Stockage: dense granule secretory
proteins.
 Release:
In neurons: The realease is induced by
depolarization via a calcium-dependant
mechanism.
In plasma: excessive fat intake increases plasma
neurotensin release.

8. DEGRADATION
 Neurotensin is metobolized by liver then eliminated by renal
system.
 The neuropeptide is quickly inactivated putting an end to the
transmission of the message.
Inactive fragments

9. NEUROTENSIN RECEPTORS
 NTSR1 receptor :
 Highest affinity to neurotensin.
 Made of 418 amino-acids.
 Fixation on the neurotensin receptor causes conformational changes of
the intracellular domains allowing them to interact with the G protein

10.  NTSR2 receptor :
 Made of 410 amino-acids.
 Has high homology with the NTSR1 (about 64%).
 Low affinity to neurotensin.
 NTSR3 receptor :
 Has a single transmembrane domain.
 Localized mainly in the cytoplasm (90%).
 It is not specific to the neurotensin and has the property
to bind other ligands.
NEUROTENSIN RECEPTORS

11. DISTRIBUTION
Nearly 85% of neurotensin is found
particularly in the gastrointestinal tract
in the distal part of the jejunum.
About 10% of neurotensin is expressed
in the central nervous system.
SNC

12. DISTRIBUTION OF THE NTSR1 IN THE RAT’S BRAIN

13. STUDY OF AGONISTS AND ANTAGONISTS OF
THE NEUROTENSIN
 Antagonists :
 SR48692 :
Specific antagonist with high affinity for the NTSR1 receptor and
low affinity for the NTSR2 receptor.
 Levocabastine :
Antagonist that binds only to the NTR2 receptor.
Compounds Ki hNTR1, nM Ki hNTR2, nM
Neurotensin 0,22 ± 0,04 1,44 ± 0,17
SR48692 4,3 ± 2,1 418 ± 82,2
Levocabastine No affinity 166 ± 15,5

14.  Agonists :
 PD149163 (PD)
- Selectif agonist of NTSR1 receptor.
-- Cross the Blood-Brain Barrier
-- Has similar properties with antipsychotic drugs (APD).
- NT69L
- Binds with equal affinity to both receptors and NTSR1 NTSR2
receptors.
Has the property to block the sensitization induced by nicotine.
STUDY OF AGONISTS AND ANTAGONISTS OF
THE NEUROTENSIN

15. I- NEUROTENSIN FUNCTIONS

17. neurotensin effects
 Hypothermia
 Hypolocomotion
 Analgesia
 Modulation of
acute pain
 Antinociceptiv
effect
No study has
mentioned a
possible role for
the NTS3 receptor
in pain.
NTS1 NTS2 NTS3

18. NEUROTENSIN (NT) : DISEASE AND
THERAPIES

19. NT AND PARKINSON’S DISEASE

20.  Neurotensin is involved in the regulation of dopaminergic
nigrostriatal tract.
 Pathological symptoms in PD subjects:
Compensatory increase of NT rates
Decrease in expression
of the mRNA encoding
the NTR1.
Significant decrease in neurotensin
binding sites in the substantia nigra,
ventral tegmental area, caudate
nucleus and putamen

21. An i.c.v injection of NT or D-
Trp11NT significantly
reduces two major
parkinsonian symptoms:
- muscle rigidity
- tremor
but not hypokinesia
 In the model of Parkinson lesioned rats:

22. NT AND SCHIZOPHRENIA

23. o NT may act to inhibit
dopamine
neurotransmission, in
the same manner as
antipsychotics
(neuroleptics) or drugs.
o The symptoms of
schizophrenia are partly
an NT deficit in the brain
leading to excessive
dopamine
neurotransmission.
• The NT levels in the cerebrospinal fluid (CSF) is lower in a subgroup of
subjects with schizophrenia in comparison with the control group

24. OTHER DISEASES

25. NT involvement in the
central control of blood
pressure
NT and eating disorders NT and cancer
• Hypotension was the first
NT physiological effect
ever reported
• In spontaneously
hypertensive rats, there is
a decrease of NT
concentrations in the
regions involved in the
regulation of blood
pressure: the
hypothalamus, medulla,
pons, pituitary and
spinal cord
•NT injected into the VTA
or in the ventromedial
portion of hypothamalus
decreases food intake
•The NT expression is
increased in the
hypothalamus anorexic
animals
•NT could play a role in
regulating the cell cycle
• NT has been associated
with tumor progression
and differentiation of the
periphery and the central
nervous system

26. RÉFÉRENCES :
 Fredrickson P, Boules M, Stennett B, Richelson E., (2014) : Neurotensin agonist
attenuates nicotine potentiation to cocaine sensitization, Behavioral Sciences,
4(1):42-52. doi: 10.3390/bs4010042.
 Mohamad Y. (2012) : Etude des relations entre les mutations EGFR/KRAS et les
altérations de la voie p53/p14arf et caractérisation d'une nouvelle cible
thérapeutique, le complexe neurotensine et son récepteur1, dans les cancers
bronchiques à petites cellules, Thèse de doctorat de l’universite Pierre et Marie
Curie - Paris VI, 255p.
 Richard F, Barroso S, Martinez J, Labbé-Jullié C, Kitabgi P., (2001): Agonism,
inverse agonism, and neutral antagonism at the constitutively active human
neurotensin receptor 2, Molecular Pharmacology; 60(6):1392-8.
 St-Gelais & al (2006) , The role of neurotensin in central nervous system
pathophysiology: What is the evidence?, J Psychiatry Neurosci. 2006 Jul;
31(4): 229–245.
 ZSÜRGER, La neurotensine : un peptide modèle pour l'étude de la
neurotransmission, disponible sur
http://www.123bio.net/revues/nzsurger/ia_4.html , consulté le 15-03-2015

27. THANK YOU ALL ! 