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GASTROINTESTINAL PEPTIDES
R. P. KOROLKIEWICZ, M.D., Ph.D.
Z. KONSTANSKI, M.D.
Department of Pharmacology
Medical University of Gdańsk, Poland
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Motilin
Structure: 22 aa peptide isolated from upper small
intestine entire molecule required for full
biological activity
Synthesis: small intestine endocrine cells, pituitary and
pineal glands
Circulating levels: variable, depend on duodenal
motility, meals inhibit release of motilin
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GASTROINTESTINAL PEPTIDES
R. P. KOROLKIEWICZ, M.D., Ph.D.
Z. KONSTANSKI, M.D.
Department of Pharmacology
Medical University of Gdańsk, Poland
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Motilin
t1/2= 5 min
Elimination: kidneys
Action in fasted animals: muscle
contraction of LES,
stomach, duodenum
Receptor agonists: erythromycin
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Motilin
Human motilin precursor: 115 aa
25 aa signal
peptide 66 aa
MAP
Motilin mRNA: duodenum
Function: regulates interdigestive migration
complexes
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Amino acid sequences of galanin
1 5 10 15 20 25 29
GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlavalglyasnHisArgSerPheserAspLysasnGl
yLeuthrser
GlyTrpThrLeuAsnSerAlaGly
TyrLeuLeuGlyProHisAlaileaspasnHisArgSerPhehisAspLystyrGlyLeuAlaNH2
GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlaileaspasnHisArgSerPheserAspLyshisGly
LeuThrNH2
Human
Pig
Rat
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Biological actions: contraction of colon,
defecation
inhibition of pentagastrin-stimulated
acid secretion
stimulation of
exocrine pancreatic secretion
increased blood flow, capillary permeability
Dumping syndrome: neurotensin release
Neurotensin
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NT: 13 aa from bovine hypothalamus
NmN: 6 aa from porcine spinal cord
Xenin: 25 aa from human gastric mucosa
NT: widely spread in the body
Release stimulant: meal (fat)
t 1/2 = 1.2-6 min.
Receptors: 3 types capable of increasing cGMP, cAMP and inositol levels
Neurotensin (NT), neurmodulin (NmN),
xenin
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GRP : heptacosapeptide, porcine stomach
Neuromedin B, C: porcine intestines, spinal cord Gene location: chromosome 18
Structure: 23-aa signal peptide, 27-aa GRP 95-aa extension peptide
Distribution: GI tract, CNS, peripheral nervous system
Gastrin-releasing polypeptide (GRP), bombesin-like peptides neuromedin B, C
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GRP-bombesin: bombesin=neuromedin
C=GRP>neuromedin B
Neuromedin B: neuromedin B>GRP, bombesin
BRS-3: GRP, bombesin > neuromedin B
Biological actions: gastrin, PP, CCK, PYY, insulin
release
mitogens for cell proliferation, tumor growth
factor, inhibition of food intake, satiety
GRP; bombesin-like peptides; neuromedin receptors
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Galanin (Gal)
Gal: 29 or 30 aa peptide
Isolation: pig upper intestinal extracts
Structure of human Gal
1 5 10 15 16 20 25G W T L N S A G Y L L G P H A V G N H R S F S D K N G L T S
-
- C - N - H - C - N -
- -O H - C - O - H
-
O
-H
-
O--
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Galanin
t1/2 in nervous tissue: 100 - 120 min
Reasons for stability: specific horse-shoe
aligment of the N-and C-
terminal portions
Important pharmacophores: Gly, Trp, Asn,
Tyr, Leu
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Galanin antagonists
Where does the idea come from
Structure
Drawbacks: peptide nature
lack of blood-brain
barrier penetration
peptidase sensitivity
agonist-like effects
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Galanin PreproGal: chromosome 11 (11q 13.3-13.5)
PreproGal: Galanin + GMAP
Regulation of Gal gene expression: steroids
(oestrogens) thyroid hormones NGFperipheral nerve injury
protein kinase C
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Galanin actions
Stimulation of food intake (esp. pure fat)
Alzheimer’s and Parkonson’s disease:
impairment of memory
role of Gal antagonists
Role in neuronal damage: periphery trophic
activity CNS
inhibition of EAA release
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Galanin effects The influence of Gal on the adrenergic
noradrenergic systems serotonergic
Nociception
Neoplasmatic trophic factor
Hyperglicaemic agent
Cardiovascular action
Smooth muscle
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Guanylin, uroguanylin, lymphoguanylin
Guanylin: isolated from rat jejunum
Uroguanylin: isolated from opposum urine
Rceptor(s): guanylyl cyclase
Function: regulation of intestinal, renal fluid & electrolyte transportation
Location: guanylin-intestine (distal colon) uroguanylin-stomach, kidney, lung, pancreas, intestine lympohguanylin-kidney, myocardium, immune
system
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Sorbin
Isolation: porcine intestinal extracts
Function: increases water & sodium absorption in the intestine and in the gallbladder Monitor peptide, luminal CCK-releasing factor Isolation: rat pancreatic juice & small intestine
Function: CCK release in response to food growth stimulation of
fibroblasts, pancreatic tumor cells
Cleavage: lumenal trypsin
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Peptide families
Gastrin-CCK CCK
gastrin
Secretin-glucagon-VIPsecretin
glucagon PHI, GIP, VIP,
PACAP, GLP17-36
Pancreatic polypeptidepancreatic
polypeptide
neuropeptide Y
peptide YY
OtherGRPmotilin galanin neurotensin somatostatin
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Peptides as endocrine, neurocrine or paracrine substances
ENDOCRINE NEUROCRINE PARACRINE Somatostatin Somatostatin
Somatostatin
Cholecystokinin CCK Peptide YY
Gastrin GRP
Secretin Opioids
Insulin Substance P
Glucagon VIP
Enteroglucagon Neuropetide Y (NPY)
Pancreatic polypeptide Neurotensin
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Peptides as endocrine and neurocrine substances
ENDOCRINE PEPTIDES NEUROCRINE PEPTIDES Neurotensin
Motilin
Pancreastatin
Glucose-dependent insulinotropic Galanin
peptide (GIP) Motilin
Peptide YY (PYY) Peptide YY
Urogastrone/
epidermal growth factor
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Somatostatin (SST)
Preprohormone: 119 aa
Stimulation of expression: cAMP
Bioactive peptide: tissue specific different length-
gastric antrum, pancreatic islets
(14 aa), small intestine (28 aa)
Receptors: SST1-5, some coupled to G proteins
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Somatostatin (SST)
Function: negative feedback on acid secretion
Use: gastrointestinal bleeding from esophageal
varices
diarrhoea (Crohn’s diseases, HIV, short
bowel syndrome)
endocrine tumors (e.g. VIP secreting)
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Arguments in favour of multiple Gal receptors in native systems
Binding profiles: different affinities in various
tissues
Interactions with multiple signal transduction
pathways
M40, M15, M35 or C7 can act as agonists,
partial agonists or antagonist in different
systems
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hGAL1 receptor Isolated: human Bowes melanoma cells
Structure: 349 aa coupled to Gi/o proteins
Mapping: 18q23
Location: foetal brain, GI tract, Bowes melanoma
Plasticity : hypothalamic GAL1 mRNA elevated more in females than males, varies across oestrous cycle
Function: cAMP concentration, opens inwardly rectifying K+ channels, stimulates MAPK
Pathology: children with growth insufficiency
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gal2
Isolation: rat
Structure: cloned hgal2 387 aa, 15 aa more than rat in C terminal 85% similarity between rat and human
Distribution: widely spread in central and peripheral tissues
hypothalamus
pituitary
cerebral cortex
lung
hippocampus
amygdala
heart
GI tract
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Pharmacological profile: high affinity for full-length & N-terminal Gal fragments
Coupling: Gq/11 positive effects on Ca2+ influx and exocytosis Gi/Go inhibition of exocytosis
The effect depends on the host cell or G-protein repertoire
gal2
Intracellular signalling: stimulation of phospholipase C intracellular Ca2+ mobilization Ca2+-dependent Cl- channel activation can inhibit cAMP accumulation
Pathology: hereditary neurologic amyotrophy Russell-Silver syndrome protection in Alzheimer’s disease ()
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gal3
Isolation: rat
hgal3 was cloned
from a genetic library based on
structural similarity to hGAL1, gal2
Location: 22q 12.2-13.1
Structure: hgal3 368 aa
90% similarity of human to
rat
Tissues: heart, spleen, testes
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Coupling: Gi/Go
Pharmacology: combination of GAL1 and gal2
Actions: activation of inward K+ current,
hiperpolarization consistent with
inhibition of exocytosis, control of
emotions, feeding, pituitary hormones release,
nociception, metabolism, insulin,
glucose homeostasis
gal3