Transcript Bez tytułu slajdu - British Pharmacological Society

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,
 Receptor agonists:
stomach, duodenum
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
GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlavalglyasnHisArgSerPheserAspLysasnGlyLeuthrser
Human
GlyTrpThrLeuAsnSerAlaGly TyrLeuLeuGlyProHisAlaileaspasnHisArgSerPhehisAspLystyrGlyLeuAlaNH2
Pig
GlyTrpThrLeuAsnSerAlaGlyTyrLeuLeuGlyProHisAlaileaspasnHisArgSerPheserAspLyshisGlyLeuThrNH2
Rat
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
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 =
 Receptors:
1.2-6 min.
3 types capable of  increasing cGMP,
cAMP and inositol levels
Gastrin-releasing polypeptide (GRP), bombesin-like peptides
neuromedin B, C
 GRP :
heptacosapeptide, porcine stomach
 Neuromedin B, C: porcine intestines, spinal cord
 Gene location:
 Structure:
 Distribution:
system
chromosome 18
23-aa signal peptide, 27-aa GRP
95-aa extension peptide
GI tract, CNS, peripheral nervous
GRP; bombesin-like peptides; neuromedin receptors
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
Galanin (Gal)
 Gal: 29 or 30 aa peptide
Isolation: pig upper intestinal extracts
Structure of human Gal
1
5
10
15 16
20
25
GWTLNSAGYLLGPHA VGNHRSFSDK NGLTS
-
O
O H
-
-C-O-H
-
O H
-C-N-H
- C-N-
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
NGF
peripheral
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:
pancreatic
CCK release in response to food
growth stimulation of fibroblasts,
tumor cells
 Cleavage: lumenal trypsin
Peptide families
Gastrin-CCK
Secretin-glucagon-VIP
secretin
glucagon
PHI, GIP, VIP,
PACAP, GLP17-
CCK
gastri
n
Pancreatic polypeptide
pancreatic polypeptide
neuropeptide Y
peptide YY
Other
GRP
motilin
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)
Peptide YY (PYY)
Urogastrone/
epidermal growth factor
Motilin
Peptide YY
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 
hippocampus
pituitary 
amygdala
cerebral cortex 
heart
lung 
GI tract
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
The effect depends on the host cell or G-protein repertoire
 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
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