Hormonal Regulation of the GI Tract PDF

Hormonal Regulation of the Gastrointestinal tract 10 µm 10 µm Dr Stephen Kelley Professor John Peters...

Hormonal Regulation of the Gastrointestinal tract 10 µm 10 µm Dr Stephen Kelley Professor John Peters E-mail [email protected] TEMs of resting (left) and stimulated (right) parietal cells from piglet stomach from: Handbook of Physiology – The Gastrointestinal System III (1989). Cell biology of hydrochloric acid secretion. Forte, J.G and Soll, A.  Learning Objectives Following this lecture and additional study students should be able to: Ø Outline the gross anatomy and mechanical functions of the stomach Ø Describe the process of gastric emptying and its controls Ø List the gastric gland secretions and their functions Ø Draw a diagram showing how HCl is produced and how this is regulated Ø Describe the 3 phases of gastric secretion and the nature of their controls Ø Understand the overall mechanism by which acetylcholine, histamine and gastrin enhance the activity of the H+/K+ATPase (‘proton pump’) to promote the secretion of HCl Ø Understand hormonal control of the activity of the small intestine Ø Understand how the pancreas exerts control of the GI tract via endocrine and exocrine mechanisms. Recommended reading: o Boron, Boulpaep (2017). ‘Medical Physiology, 3rd. ed.’. Chapter 42.  The Stomach Ø J – shaped bag: 50 >1000 ml capacity: orad region relaxes receptively (driven by vagus) to accommodate food from oesophagus Ø Starting point for digestion of Storage proteins (by pepsin and HCl), continues carbohydrate digestion (by salivary amylase) Propulsion/ Ø Mixes food with gastric Grinding secretions to produce semi- liquid chyme Ø Limited amount of absorption Adapted from Ø Stores food before passing it into small intestine as chyme for further digestion and absorption Ø Secretes approximately 2 litre/day of gastric juice from gastric glands in the gastric mucosa  Mechanical Activity of the Stomach Ø Occurs as two types: orad stomach (fundus and proximal body) – tonic, i.e. maintained caudad stomach (distal body and antrum) – phasic, i.e. intermittent Orad stomach Caudad stomach Adapted from  Control of Stomach Emptying Ø Strength of antral wave, or pump, and the opening of the pyloric sphincter determine the delivery of chyme to the duodenum Governed by: o gastric factors o duodenal factors Gastric factors Ø Rate of emptying proportional to volume of chyme in stomach Distension increases motility due to: o stretch of smooth muscle o stimulation of intrinsic nerve plexuses o increased vagus nerve activity and gastrin release Ø Consistency of chyme Emptying facilitated by thin liquid chyme  Duodenal Factors Ø Duodenum must be ready to receive chyme: delays emptying by: o Neuronal response: the enterogastric reflex – decreases antral activity by signals from intrinsic nerve plexuses and the ANS o Hormonal response – release of enterogastrones [e.g cholecystokinin CCK)] from duodenum inhibits stomach contraction Ø Stimuli within the duodenum that drive the neuronal and hormone responses include: o Fat – particularly potent – delay in gastric emptying required for digestion and absorption in small intestine o Acid – time is required for neutralization of gastric acid by bicarbonate secreted from the pancreas – important for optimal function of pancreatic digestive enzymes o Hypertonicity – products of carbohydrate and protein digestion are osmotically active and draw water into the small intestine – danger of reduced plasma volume and circulatory disturbances (e.g. ‘dumping syndrome’) o Distension  Secretory Activity of the Stomach Ø For considerations of secretion the mucosa of the stomach is classed as: the oxyntic gland area (proximal stomach including the fundus and body) the pylorlic gland area (distal stomach, designated the antrum) Gastric mucosa is composed of: o a surface lining the Oxyntic muscosa stomach (OM) o pits, invaginations of the surface Pyloric gland area o glands, at the base of (PGA) the pits responsible for several secretions Adapted from  Secretions of the Gastric Glands Gastric pit OM PGA Mucosa Chief cell pepsinogen Gastric gland Hormone, to blood Paracrine G cell Gastrin Parietal cell, D cell, Hydrochloric acid Hormone, Enterochromaffin- Somatostatin Intrinsic factor to blood like cell, Gastroferrin Histamine Pyloric gland area (PGA) Oxyntic mucosa (OM) antrum fundus and body  Functions of the Gastric Secretions Ø HCl Oxyntic mucosa (fundus and body) o activates pepsinogen to pepsin o denatures protein o kills most (not all) micro-organisms ingested with food Ø Pepsinogen o inactive precursor of the peptidase, pepsin. Note: pepsin once formed activates pepsinogen (autocatalytic) Ø Intrinsic factor and Gastroferrin o bind vitamin B12 and Fe2+ respectively, facilitating subsequent absorption Ø Histamine o stimulates HCl secretion Ø Mucus o protective Pyloric gland area (pylorus and antrum) Ø Gastrin o stimulates HCl secretion and motility Ø Somatostatin o inhibits HCl secretion Ø Mucus o protective Interstitium Gastric q A- Chloride- Lumen Bicarbonate K+ Exchanger Parietal 2K+ 2K+ cell q P- H+/K+ ATPase (proton pump) 3Na+ 3Na+ q N-Na-H Exchanger (NHE) Cl- Cl- Cl- q CA- Carbonic A Tubulovesicle with proton pump when the parietal is cell resting anhydrase Water will enter the P K+ HCO3- HCO3- K+ parietal cells via Parietal cell is aquaporins. Na+ Na+ P HCl H2CO3 stimulated When the parietal cell N CA H+ H+ is stimulated, H+ is H+ transported into the H+ gastric lumen via the CO2 H2O CO2 H2O H+/K+ ATPase on the apical membrane. Interstitium G cell 1) ACh is released by Gastric parasympathetic cholinergic Lumen neurons binding to muscarinic (M3) ACh Parietal receptors on parietal cells cell with subsequent activation of PLC CCK2 2) Gastrin is released by G cells and binds to CCK2 + receptors on parietal cells PLC Cl- Cl- with subsequent activation + + of PLC mAChR 3) Histamine is secreted by P K+ the enterochromaffin-like K+ AC cells in the gastric glands in + + response to stimulation by P HCl acetylcholine. Histamine H2R H+ binds to H2 receptors with H+ subsequent activation of adenylyl cyclase increasing cAMP. All 3 pathways allow for H+/K+ATPase to traffic to the Enterochromaffin-like cell apical membrane.  Secretagogues Cause Trafficking of the H+/K+ATPase http://mcb.berkeley.edu/ labs/forte/morphol.html H+ H+ Canaliculus H+ Extended H+ H+ microvillus M3 H+ M3 ACh H+ G G H+ Gastrin Protein + H2 H2 kinases Histamine Tubulovesicle Resting state of the parietal cell – Stimulated state of the parietal cell – H+/K+ATPase is largely within cytoplasmic H+/K+ATPase traffics to the apical membrane tubulovesicles taking residence in extended microvilli Interstitium Somatostatin is Gastric secreted by D cells in Lumen the gastric glands Parietal Somatostatin binds to cell SST2R receptors, inhibiting adenylyl cyclase The decrease in cAMP Cl- Cl- results in decrease gastric acid secretion P EP3 from parietal cells as it - prevents trafficking of - K+ K+ H+/K+ATPase to the AC apical membrane. - P HCl Prostaglandins also SST2R inhibit gastric acid H+ H+ secretion by the same mechanism. D-cell The Three Phases of Gastric Acid Secretion Ø Rate of gastric secretion is controlled by stimulatory and inhibitory mechanisms that occur in three overlapping phases Ø Cephalic phase (‘in the head’) – before food reaches the stomach preparing it stomach to receive food driven directly and indirectly by the CNS and vagus nerves (CN X) Ø Gastric phase – when food is in stomach involves both physical and chemical mechanisms Ø Intestinal phase – after food has left stomach chyme entering the upper small intestine causes weak stimulation of gastric section via neuronal and hormonal mechanisms (not discussed further)  The Cephalic Phase Enteric - ­ACh D cell Slight, smell, taste of food. Conditioned neurone Increased reflexes, chewing, swallowing + ¯ss secretion ­gastrin (in blood) - + Vagal + Enteric + + Parietal ­GRP activation neurone G cell cell + + + Enteric neurone ­ACh + + Enteric ­ACh ECL cell ­histamine neurone ss, somatostatin; GRP, gastrin releasing peptide Ø Vagus stimulates enteric neurones that: release ACh directly activating parietal cells (neurotransmitter action) via release of GRP causes release of gastrin from G cells in to systemic circulation that activates parietal cells (endocrine action) via release of histamine from ECL cells that locally activates parietal cells (paracrine action) via inhibition of D cells decreases the inhibitory effect of ss on G-cells  The Gastric Phase Distension Via mechanoceptors Protein digestion products Enteric - ­ACh D cell Slight, smell, taste of food. Conditioned neurone Increased reflexes, chewing, swallowing + ¯ss - secretion ­gastrin (in blood) ↑pH - + + + Vagal + Enteric + + Parietal ­GRP activation neurone G cell cell + + + Enteric + neurone ­ACh + + ­ACh Enteric ECL cell neurone ­histamine ss, somatostatin; GRP, gastrin releasing peptide Ø distension of stomach activates reflexes that cause acid secretion Ø food buffers pH, D cell inhibition via ss of gastrin release is decreased Ø amino acids (e.g. tryptophan, phenylalanine) stimulate G cells. Other stimulants include: Ca2+, caffeine and alcohol  Inhibition of Gastric Acid Secretion Ø Once more involves cephalic, gastric and intestinal phases Ø Cephalic phase vagal nerve activity decreases upon cessation of eating and following stomach emptying† Ø Gastric phase antral pH falls when food exits stomach (due to decreased buffering of gastric HCl) – release of somatostatin from D cells recommences, decreasing gastrin secretion prostaglandin E2 (PGE2) continually secreted by the gastric mucosa acts locally to reduce histamine- and gastrin-mediated HCl secretion Ø Intestinal phase The factors that reduce gastric motility also reduce gastric secretion (e.g. neuronal reflexes, enterogastrones) †pain,nausea and negative emotions also decrease vagal nerve activity (parasympathetic) and increase sympathetic activity that combined reduce gastric acid secretion Secretions of the Small Intestine – hormones (1) Ø Small intestine secretes (into the blood) various peptide hormones from endocrine cells within the mucosa: Ø Gastrin – from G cells of gastric antrum (mainly) and duodenum stimulates H+ secretion by gastric parietal cells stimulates growth of gastric mucosa (a trophic effect) Ø Secretin – from S cells of duodenum, released in response to H+ and fatty acids in lumen promotes secretion of pancreatic and biliary HCO3- Ø Cholecystokinin (CCK) – from I cells of duodenum and jejunum, released in response to monoglycerides, free fatty acids, amino acids, small peptides in lumen inhibits gastric emptying causes secretion of pancreatic enzymes required for digestion stimulates relaxation of sphincter of Oddi and contraction of gall bladder to eject bile into duodenum potentiates the action of secretin Secretions of the Small Intestine – hormones (2) Ø Glucose-dependent insulinotropic peptide (GIP, aka gastric inhibitory peptide)* from K cells of duodenum and jejunum, released in response to glucose, amino acid and fatty acids stimulates release of insulin from pancreatic β-cells (incretin action) inhibits gastric emptying Ø Glucagon-like peptide-1 (GLP-1)* from L cells of the small intestine stimulates insulin secretion inhibits glucagon secretion from pancreatic α-cells decreases gastric emptying and appetite Ø Motilin – from M cells of duodenum and jejunum, secreted during fasting state initiates the migrating motor complex Ø Ghrelin – from Gr cells of the gastric antrum, small intestine and elsewhere (e.g. pancreas) stimulates appetite Ø All peptide hormones act on G-protein coupled receptors *Incretins act upon the ß-cells of the pancreas in essentially feed-forward manner to stimulate the release of insulin  Secretions of the Small Intestine (Juice) Ø Succus (juice) entericus (of the intestine) – approximately 2 litre secreted per day - composition varies throughout small intestine Ø Control mechanisms include § Distension/irritation, gastrin, CCK, secretin, parasympathetic nerve activity (all enhance), sympathetic nerve activity (decreases) Ø Secretion lacks digestive enzymes, but contains § mucus – for protection/lubrication (from goblet cells) § aqueous salt - for enzymatic digestion (mostly from the crypts of Lieberkühn) Interstitial space Lumen Secretion involves Na+/K+ ATPase Na+/K+/2Cl- co-tranporter Chloride channel (CFTR) Nb. Excessive activity causes secretory diarrhoea (as in cholera) – see BS31013 Biomembranes tutorial  Pancreatic Secretions Ø Endocrine – insulin and glucagon – secreted to blood Ø Exocrine – digestive enzymes (acinar cells), aqueous NaHCO3- solution (duct cells) – secreted to the duodenum collectively as pancreatic juice  Secretion of the Pancreatic Duct Cells Ø Duct cells secrete 1 – 2 litre of alkaline (HCO3- - rich) fluid into the duodenum per day. Note HCO3- content is highest at high secretion rates Ø Neutralises acidic chyme entering the duodenum § provides optimum pH for pancreatic enzyme function § protects the mucosa from erosion by acid Secretion involves Interstitial space Lumen Na+/K+ ATPase Na+ HCO3- Na+/H+ exchanger K+ HCO3- K+/H+ ATP-ase Ductule HCO3- (proton pump) Na+ Na+ H2CO3 Cl- Na+/HCO3- Cl- cotransporter H+ Carbonic Cl-/HCO3- anhydrase exchanger K+ CO2 + H2O Chloride channel CO2 Na+, H2O (CFTR)* Na+, H2O *Nb. Patients with cystic fibrosis (lack functional CFTR) have reduced fluid secretion  Secretion of the Pancreatic Duct Cells Explanation of figure At the basolateral membrane At the apical membrane facing the interstitium: facing the lumen: o HCO3- secretion occurs via a Cl- Na+/Cl- cotransporter. /HCO3- exchanger. Cl- in the lumen is Provides some of the needed for exchange. Some HCO3- HCO3- required for its secretion might also occur via CFTR Na+ (not indicated) secretion across the apical membrane HCO3- Na+/K+ATPase. K+ Maintains the electrochemical HCO3- gradients of Na+ and HCO3- K+ ions Na+ Na+ H2CO3 Cl- Na+/H+ exchanger. Cl- CFTR is a Cl- channel that Contributes to export H+ Carbonic provides an important fraction of of H+ ions liberated by the luminal Cl- needed for Cl- anhydrase /HCO3- exchange. Activated via dissociation of H2CO3 K+ second messenger systems CO2 + H2O by secretin K+/H+ATP-ase (proton CO2 pump). Contributes to Na+, H2O Na+, H2O export of H+ ions liberated by dissociation of H2CO3 Note: in the interests of clarity, a K+ channel on the basolateral membrane that mediates export of ‘excess’ K+ ions due to transport processes is not shown. Also, water may cross both basolateral and apical membranes via ‘water channels’ (aquaporins, not shown)  Control of Pancreatic Secretion Three phases: § Cephalic – mediated by the vagal stimulation of mainly the acinar cells (20% total secretion) § Gastric – gastric distension evokes a vagovagal reflex resulting in parasympathetic stimulation of acinar and duct cells (5-10% total secretion) § Intestinal (see below; 70-80% of total secretion) Acid in duodenal Fat and protein in lumen duodenal lumen ­ Secretin release ­ CCK release from from S cells I cells Secretin carried by blood Neutralizes CCK carried by blood Digests Pancreatic duct Pancreatic acinar cells cells ­ Secretion of ­ Secretion of aqueous NaHCO3 digestive enzymes solution into into duodenal duodenal lumen lumen  Pancreatic Enzymes Ø Can completely digest food in the absence of all other of enzymes Acinar cells Duodenum Enzymes stored in zymogen granules and released in response to elevated [Ca2+]i Enterokinase (mucosal cells) Proteases Trypsinogen Trypsinogen Trypsin + Autocatalysis Chymotrypsinogen Chymotrypsinogen + Chymotrypsin Procarboxypeptidase Procarboxypeptidase + Carboxypeptidase A and B A and B A and B Amylases Pancreatic amylase Pancreatic amylase Inactive enzyme Lipases Active enzyme Pancreatic lipase Pancreatic lipase