CH 10-G tract

GI

Muscosal endocrine cells in gut Secrestes hormones=enteroendorcrine

Not in discrete bodies but fdiffused


of mucos, muscularis mucosa, submucosa, circular muscles, longitudinal muscles and serosa

2 types

Enterochromaffin (EC) cells
• Most common neuroendrocine G1 cells in jejunjum. Ileum, appendix, colon and rectue
Source of serotonin and substance P
•ECL cells: histamine secreting cells in gastric mucose, cannot produc serotonin (from gut endoderm and process amine percusors by decarboxylation (APUD)
• Chromaffin cells in adrenal meduua are of neural orginin, procude acteholomnes


Argyrophilic cells
• Nueroendoricne cells, become dark I silver stainining, more nuermous than EC cells, secrete different peptide hromones

enteric

Myenteric/auerbach’splexus; between circular and lontifutial muiscles, responsible for peristaltic movments and gut motility, motor movments indluced y symp and para inpiuts for relaction/contrction
• Submucosal or me


issner’s plexus: in submucosa, provides secrtomoto input to mucosal surface, controls villi movmemnt

GI hormones

• Ecreted by 12 cell types
• G cells: gasrtin
• S cells; secrtein
• I CELLS: Cholectolkin (CKK)
• L cells: glucagon like peptides (GLP-1 and 2)
• A cells: glucagon
• K cells – Gastrin-inhibiting Polypeptide (GIP)
• D cells – Somatostatin (SST)
D1 cells – Vasoactive Intestinal Polypeptide (VIP)
• D2 or F cells – Neuropeptide Y (NPY), Pancreatic Polypeptide (PP) and Peptide YY (PYY)
• EC1 cells – Substance P, Histamine
• EC2 or M cells – Motilin
• N cells-neurotensin

hormone families

Gastin family: gastrin, CCK

Secretin family: secrein, VI[, GIP, glucagon

Pancreatic Polypeptide family: NPY, PP, PYY
•
• Tachykinin family: Substance P
•
• Others: Motilin, Neurotensin, SST and GRP, CGRP

endocrine

Gastrin, CCK, Secretin, GIP, Motilin, SST, PP, Neurotensin, PYY

neurocrine

: CCK, VIP, SST, Substance P, GRP, NPY, CGRP

paracrine

SSt

gastrin family

Amino acid peptide
G14-mini gastrin
G17-little gastrin’
g34: big gastrin
• 90% of g cells secrete g17

G17 and CCK have te same 5 amino acid C terminal, both bind to C-termonus pentappedie
G17 has tyrosine at psoptn 6 (does not need to be sulfated) but pstopn 7 has to be sulafted
• 50% of g17 is sulfated


• Sulfated CCK is 160x more potent, binds to CCKa receptor

CCK b recpeots are less speoifc and do not need sulfation, also a gastrin receptor for acid secretion from parietal cells

gastrin secretion stimulated by

giestted proteins, peptides and amino acids

Also in responses to electrical vagal sitnuaton through neuorns using GRP neurotrnmistters

gastrin inhbitted

• Atropine inhbits meal gastrin release, also SST inhbits

actions of gastrin

Stimulates gastric acid (stomach) secretion. Parietal cells growth in muscosa

Binds to g protein coupled recpeot (CCKB), or can indirectly release histamine from ECL cells to act

Bidning to gastrin receptor via IP3 increases Ca and activates PKC

Hypergastrinimera cuases ECL cell hyperplasia /carcinoid tumor

Gastrin increases mucosal blood flow, pepsin release, contration of lower spinger and gall bladder

Cholescystokinin (CCK)

• Ivy and oldberg: found that fat insitallion causes gall bladeer to contract==caused by CCK
• CCK expressed in 1-cells, peptide
• CCK 58, CCK 39, CCK 33, and CCK 8(active c terminus)
• Has ytosine at posption 7=fully sulfated

CCk 8 is fully active, homology with gastrin,

secretd by I cells in duondenum and proximal jejunum,

cleared by liver so it has no effective endcrine role,

used by CNS in mysentic nerve plecus in nerves to placnreas, urinar bladeer and uterus
• Major form in cirucltion: CCK 33

CCK secretion

Secretion situmlated by intraduoudnetal protein, fat, amino acids: pehnluaniane and tyrosine, CCK-releasing factor into instetine


Secretion inhbited by SST

actions of CCK

Causes postprandial gall bladder contraction and bile release into duodenum whe spicnher of oddi relaxes ast the release of VIP/NO


Stimulates release of enzyme pancreatic uice and secretin induced carbonate rich pancreatic uice

Stimulates tophic growth of pancreasic acinar cells

Inhbits gastric empying by Relaxing proxomal stomach and contracitnt pyloric spinvher
•

Mediates food intake in humans via CCKa rreceptors = insuced slower gatric empltying

STimylated vagus nerve

Ghrelin: increases apeptide inhbits vagus

Low CCk secretion: bulimia nervosa: disturbed eating patterns

Impaired secretion of CCK in response to meal===unctrolled eating

secretin

• First hormone to be indieitifed, named by bayliss and starling
• Secreted by S cells, long single chain peptide
• 14 amino acids like glucgon
• Acts vua cAMP and g protein seven protein receptor
• No tyrosine= hard to qaunitfy

actions of secretin

SST inhbuts secretin
CCK stimulates secretin

levels Rise after eating= Stiumate release of secretin: acid (4.5)
Secretin stiulates release of biocrbaoate pancreatic juice to nutelize acidity in intensine
Not influenced by fat, aclhochol or amino acids, or vagotmoy or atropine
•

Gastric inhibitory peptide (GIP)

• No rsides
• Encoded in K cells
• Play role in CNS for memory (hippocampus) and regulation of appetide 9hypothamalus)
• Acts bua g prtien recpeots in islet B cells


incretin family

GIP needs glucose to work= glucose-dependent insulinotropic peptide (GIP dependent

GIP actions

• Stimulates insulin secretion
•GIP rises in response to more glucose in diet and stimulate insulin
•Gastric effects used with carobsy terminal
r inhibition of apopsos of islet B cels, s
itumlates pancreatic water/electrolyte secretion,
situnlates glucagon secretion and fat accumaltion
•
Sutmlates induli induced liopgenesis :increased utilization of glucose in the muscles, activation of lipoprotein lipase in adipocytes,
•inhibition of absorption of fluids and electrolytes in small intestine,


(Cushing’s disease, chronic adrenocorticotropin (ACTH) exposure of cortisol-producing cells in the adrenal cortex, stimulates an aberrant expression of GIP receptors in these cells, leading to overproduction of glucocorticoid (cortisol)
• Overall, the GIP is an anabolic hormone.

Vasoactive Intestinal Peptide (VIP)

• Similar to secretin
• Secreted by D1 cells
• Also in other tissues, fasting levels are stabble
• Actis ua Gs recpetors using camp, using both neurcrine and paracrine methods

actions of VIP

Cause relaxation of smoth muscles of spincher and fatric fundus, treachale muscles and gall baldder

Cuases vasoditlion inn heart: inotopic an chromotopric Influences local secretion such as vaginal lubrication

Stimulate NO synthase=vasofilation in penile rection

Promotes motltiy and bloodlfow in gut

lipolysis, glycogenolysis, and intestinal, bile and pancreatic secretions.
• also regulates prolactin and growth hormone secretions from pituitary.
• The hypothalamic growth hormone-releasing hormone (GHRH) also belongs to the VIP family.

substance P

• First neuropeptide in gut
• Tackykin family
• Receptors: NK2 and NK3 (7 span protiens)
• Potent vasodilato, also neurostranmisiter

substance P actions

• Sitmultes epthila;e secretion
• Postnadal induction of propulsive motitltiy
• Natural satiatior of thirst in brain

SST

inibitory hormone,
•hypothalamic arcuate nuclei , pancreatic and intestinal D cells, s
•o cyclic peptide with a disulfide (S-S) bond.
• he pancreatic D cells secrete SST14,
•epithelial D cells of duodenum, jejunum, ileum and colon mucosa secrete SST28.
• The cytoplasmic processes of D cells in the gut terminate near gastrin-secreting G cells and HCl-secreting parietal cells, suggesting somatostatin’s tonic inhibitory influence on secretions from these cellular sources.

sst actions

• Stimulate SSt rlease: protein and dietary fat
• Inhbit ssst release :cholinergic inputs
• There is also auto-inhibition via autocrine regulation.


least five types of G protein-coupled receptors expressed in different target tissues. I

SST
inhibits insulin release by ligand binding to SST R5
blocks glucagon release via SST R2.
SST inhibits release of gastrointestinal peptides such as gastrin, CCK, secretin, VIP, motilin, GIP, insulin and glucagon.
inhibits gastrointestinal secretions, gut motility and gall bladder contractions
• . The myenteric blood flow and portal pressure decrease under SST influence. T
•
• he anti-trophic effect of SST is beneficial to humans, and the hormone is used clinically to treat both benign and metastatic gut endocrine tumors.

motlilin

• Motilin stimulates gastric motility in cyclic fashion.
• Its actions are blocked by SST.
• stimulates pepsin from gastric chief cells and pancreatic enzymes and chloride secretion.

PP

pancreatic polypeptide (PP),
peptide YY (PYY), and neuropeptide Y
(NPY).
(PP) is secreted by F- or PP-cells of pancreatic islet
• peptide YY (PYY) by cells of the colon,
•neuropeptide Y (NPY) by brain and enteric neurons, colocalized with enterochromaffin (EC) cells.

actions

neuropeptide Y functions as a neurotransmitter and stimulates food intake.
he NPY is a potent vasoconstrictor and inhibits acetylcholine release, besides increasing appetite


The PP and PYY are functional in the gut and exhibit a postprandial rise in response to dietary protein (PP) and fats (PYY)

The PP from islet F- or PP-cells inhibits pancreatic bicarbonate and protein secretion, causes relaxation of gallbladder, and inhibits gastric motility and acid secretion.

T

enteraglucagon or glucaon like peptide

pancreatic glucagon secreted by islet A cells.

The enteroglucagons, on the other hand, are secreted by L cells in the gastrointestinal tract.
•
end products include glucagon, glicentin-related pancreatic polypeptide (GRPP), glicentin, glucagon-like peptide 1 and 2 (GLP-1 and GLP-2) and oxyntomodulin,

actions

• 1 inhibits glucagon and gastric emptying,reduces food intake.
• The GLP-2 promotes cell growth in GI mucosal tract, and plays a role in short bowl syndrome and Crohn’s syndrome, both of which cause diarrhea, abdominal pain etc.

neurotensin

• the CNS, and was discovered with substance P.
• secreted by the N cells in the ileum,
• involved in vasodilation and hypotension,


secretion is stimulated by intraluminal fat,
• it binds to mast cells and causes histamine release.
• The over-secretion of neurotensin is the possible cause of dumping syndrome.

actions

•inhibition of gastric acid secretion,
nhibition of small intestinal and gastric motility


stimulation of pancreatic protein and bicarbonate secretions, stimulation of colonic motility
•

Achalasia:

• abnormal or absence of peristalsis in esophagus,
• absence of relaxation of esophageal sphincter with swallowing leading to food accumulation in esophagus.
• due to lack of vasoactive intestinal peptide (VIP)-secreting neurons in the gut,
• sphincter hypersensitivity to normal levels of gastrin resulting in prolonged contraction.

Hirschprung's disease:

congenital absence of neural ganglia in distal colon (absence of parasympathetic intrinsic ganglion cells in both Auerbach's and Meissner's plexuses – aganglionic condition) and internal anal sphincter.
• The distal colon remains contracted with no motility, while there is distension of proximal colon.
• cause is lack of vasoactive intestinal peptide (VIP)-secreting neurons in the gut, and is four times more likely to manifest in males than in females.

• Infantile hypertrophic pyloric stenosis:

congenital tonic contraction of pyloric sphincter and obstruction of gastric outlet.

lack of nitric oxide from muscles of the sphincter or a disease of inhibitory neurons of the pyloric sphincter are responsible for this condition.

Zollinger-Ellison syndrome

excessive gastrin levels, virulent peptic ulceration and acid hypersecretion.

Type I in which hyperplasia of gastric antral G cells occurs,

Type II in which gastrinomas of pancreatic islets develop, which are small, 2 to 3 mm, and hard to find.

Pancreatic cholera or watery diarrhea (Verner-Morrison syndrome):

due to excessive vasoactive intestinal peptide (VIP) in the gut leading to intestinal water secretion and diarrhea, and loss of bicarbonate and potassium, which results in metabolic acidosis.

Bulimia nervosa

The person shows recurrent episodes of uncontrolled eating. Possible cause is a lack of CCK8, which is involved in regulation of appetite.

Chronic idiopathic constipation:

This is caused by lack of motilin in the gastrointestinal tract

enkephalins

neurotransmitters in the brain. Enkephalins act to attenuate substance P release in the dorsal horn of the spinal cord and inhibit afferent pain fiber


delta opioid receptors and mu opioid receptors. Opioid recepto