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