GASTROINTESTINAL PEPTIDES R. P. KOROLKIEWICZ, M.D., Ph.D. Z. KONSTANSKI, M.D. Department of...
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Transcript of GASTROINTESTINAL PEPTIDES R. P. KOROLKIEWICZ, M.D., Ph.D. Z. KONSTANSKI, M.D. Department of...
GASTROINTESTINAL PEPTIDES
R. P. KOROLKIEWICZ, M.D., Ph.D.
Z. KONSTANSKI, M.D.
Department of Pharmacology
Medical University of Gdańsk, Poland
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
GASTROINTESTINAL PEPTIDES
R. P. KOROLKIEWICZ, M.D., Ph.D.
Z. KONSTANSKI, M.D.
Department of Pharmacology
Medical University of Gdańsk, Poland
Motilin
t1/2= 5 min
Elimination: kidneys
Action in fasted animals: muscle
contraction of LES,
stomach, duodenum
Receptor agonists: erythromycin
Motilin
Human motilin precursor: 115 aa
25 aa signal
peptide 66 aa
MAP
Motilin mRNA: duodenum
Function: regulates interdigestive migration
complexes
Amino acid sequences of galanin
1 5 10 15 20 25 29
GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlavalglyasnHisArgSerPheserAspLysasnGl
yLeuthrser
GlyTrpThrLeuAsnSerAlaGly
TyrLeuLeuGlyProHisAlaileaspasnHisArgSerPhehisAspLystyrGlyLeuAlaNH2
GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlaileaspasnHisArgSerPheserAspLyshisGly
LeuThrNH2
Human
Pig
Rat
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
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
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
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
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--
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
Galanin antagonists
Where does the idea come from
Structure
Drawbacks: peptide nature
lack of blood-brain
barrier penetration
peptidase sensitivity
agonist-like effects
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
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
Galanin effects The influence of Gal on the adrenergic
noradrenergic systems serotonergic
Nociception
Neoplasmatic trophic factor
Hyperglicaemic agent
Cardiovascular action
Smooth muscle
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
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
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
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
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
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
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)
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
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
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
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 ()
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
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