Bez tytulu slajdu

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GASTROINTESTINAL PEPTIDES R. P. KOROLKIEWICZ,
M.D., Ph.D. Z. KONSTANSKI, M.D. Department of
Pharmacology Medical
University of Gdansk, 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 Gdansk, 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 GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlava
lglyasnHisArgSerPheserAspLysasnGlyLeuthrser GlyTr
pThrLeuAsnSerAlaGly TyrLeuLeuGlyProHisAlaileaspasn
HisArgSerPhehisAspLystyrGlyLeuAlaNH2
GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlaile
aspasnHisArgSerPheserAspLyshisGlyLeuThrNH2
Human
Pig
Rat
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Neurotensin

• 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

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Neurotensin (NT), neurmodulin (NmN), xenin

• 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

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Gastrin-releasing polypeptide (GRP),
bombesin-like peptides neuromedin B, C

• 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

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GRP bombesin-like peptides neuromedin
receptors
GRP-bombesin bombesinneuromedin
CGRPgtneuromedin B Neuromedin B neuromedin
BgtGRP, bombesin BRS-3 GRP, bombesin gt
neuromedin B Biological actions ? gastrin,
PP, CCK, PYY, insulin release
mitogens for cell
proliferation, tumor growth factor,
inhibition of food intake, satiety

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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 25 G 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
O
-
-
- C - O - H

O
H
H
O
-
-
-
-
-
-
- C - N - H
- C - N -
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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 NGF peripheral
  nerve injury protein kinase C

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Galanin actions

• Stimulation of food intake (esp. pure fat)
• Alzheimers and Parkonsons 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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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 (Crohns 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
  

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gal2

• 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

• 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 Alzheimers 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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gal3

• 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