Gastrointestinal tract motility

Question 1

The GI tract is composed of the same 4 layers along its length.
- Name these 4 layers
- What layers contain the enteric nervous system.

Answer 1

1- Mucosa
- epithelium
- lamina propria
- muscularis mucosa

2- Submucosa
- Submucosal plexus

3- Muscularis externa
- Myenteric plexus (located between CM and LM) - responsible for peristalsis

4- Serosa

Question 2

Describe the structure of Smooth muscle which is found along GI tract.
- How does it structure relate to its function?

Answer 2

• Dense bodies act as attachment points for cytoskeletal proteins at points through the cell membrane.
  > Actin and myosin filaments overlap between dense bodies.
• Intermediate filaments such as desmin lie between dense bodies and act to scaffold the interaction of the thick and thin filaments.
• No T-tubules and poorly developed sarcoplasmic reticulum.
• Latch bridges
  > Specialised for long-term, maintained contraction using limited amounts of ATP.

Question 3

What is the difference between smooth muscle and skeletal muscle?

Answer 3

Smooth muscle is not striated and involves more long term contraction maintained with limited ATP whereas striated muscle is more short term powerful contractions with high ATP use

Question 4

What are the differences between the two types of smooth muscle and the need for both?

Answer 4

• Multi-Unit
• Individual fibres
• Stimulated independently
• Fine contractions
• Unitary
• Bundles of tissue
• Connected by gap junctions
• Contract as single unit
• Coordinated contractions in circumference and specific direction eg GI tube

Question 5

What is ATPase activity?

Answer 5

• Ability of myosin to hydrolyze ATP to release energy for muscle contraction.

Question 6

Describe the process of smooth muscle contraction.

Answer 6

1- Intracellular [Ca2+] increase when Ca2+ enters cell from ECF or SR
2- Ca2+ binds to Calmodulin.
3- Ca2+/ Calmodulin complex activates myosin light chain kinase (MLCK)
4- MLCK phosphorylates myosin light chains in myosin heads → increasing myosin ATPase activity (hydrolysis of ATP)
5- Phosphorylated myosin binds with actin forming cross-bridges
6- Actin slide along myosin → contraction

Question 7

How is smooth muscle contraction regulated by 2 regulatory proteins?

Answer 7

• Low Ca2+ → Caldesmon
  binds to tropomyosin & actin blocking myosin-actin binding

(Ca2+/Calmodulin complex is needed to bind to Caldesmon and Calponin to unlock the binding sites on actin)

Question 8

Describe the process of smooth muscle relaxation.

Answer 8

1- Calcium is pumped out cell or moved to intracellular stores (SR)
2- ↓ MLCK activity
3- Dephosphorylation of myosin light chain by myosin phosphatase (not calcium dependent)
4- Crossbridge formation prevented
5- Muscle relation

Question 9

What are the ways smooth muscle increases intracellular Ca2+?

Answer 9

1- Electrochemical - membrane depolarisation → opening of voltage-gated Ca2+ channels

2- Pharmacomechanical -
- Binding of endocrine messenger to receptor activates Gq protein coupled receptor
- DAG and IP3 (by PLC) produced
- DAG activates receptor activated Ca2+ channel
- IP3 binds to intracellular IP3 receptor on sarcoplasmic reticulum = Ca2+ release from SR

3- IF SR Ca2+ STORES ARE DEPLETED….
- SR Ca2+ sensor (STIM1) usually bound to Ca2+ undergoes a conformational change
- Binds to Store operated Ca2+ channel (Orai1) on plasma membrane → Ca2+ moves into the cell

Question 10

Calcium decrease in cystol can lead to 2 states which are?

Answer 10

1- Caldesmon and calponin are no longer bound to Ca2+ and bind to actin binding sites → block crossbridge cycling = NO TENSION/CONTRACTION

2. Latch Bridge State = MAINTAINS SOME CONTRACTION/TENSION IN ATP DEFICIT

Question 11

Describe how the latch bridge state is brought about.

Answer 11

1- MLCP (phosphatase) dephosphorylates the phosphorylated myosin light chains whilst still bound to actin

2- Decreases ATPase activity of phosphorylated Myosin light chain → prevents hydrolysis of ATP necessary for detachment of myosin to actin

3- Myosin is bound to actin for longer in each crossbridge cycle until ATP hydrolysis for another cycle

Question 12

What is Ca2+ independent smooth muscle contraction?

Answer 12

• Protein Kinase C Activated by DAG
  -> Activates MLCK and inhibits MLCP so the proportion of phosphorylated myosin light chains is greater
  -> sensitises the cell to contraction as the ATPase activity is greater by more phosphorylated myosin light chains = more crossbridge cycling

Question 13

What is the enteric nervous system?

Answer 13

• Works independently of any other control system to elicit local reflexes
  → Myenteric plexus – controls GI motility
  → Submucosal plexus – controls both GI motility and secretion
• CNS can also elicit effects on GIT indirectly through its stimulation of the ENS.

Question 14

How does the autonomic nervous system affect GIT.

Answer 14

-> ANS increases or decreases the likelihood of threshold being reached for action potential in ENS

• Parasympathetic – Promotes Motility/secretion
• Sympathetic – Inhibits Motility/secretion and contracts sphincters

Question 15

The rate of passage through the gastrointestinal tract can be controlled by:(2)

Answer 15

• Contraction of sphincters
• Changing the rate of peristalsis

Question 16

Coordination of the motility of the GIT as a whole is achieved by long-range neural reflexes where activity in one segments affects the motility in others.
These include the: (5)

Answer 16

1- Gastroileal reflex – Stomach activity promotes the opening of the ileocaecal sphincter.

2- **Colonoileal reflex **- Inhibits ileal emptying when the colon is stretched.

3- Gastrocolic/Duodenocolic reflexes- Food entering the stomach or duodenum promotes the motility of the colon.

4- Enterogastric reflex - Distension of the small and large intestines inhibits stomach motility and secretion.

5- Intestinointestinal reflex – over distension of one part of the intestine leads to relaxation of the rest of the intestine.

Question 17

Describe the 3 phases of deglutition.

Answer 17

1. Oral phase - Voluntary
   Food is chewed/lubricated with saliva to form a bolus. > Tongue pushes bolus to back of mouth.
   = Triggers somatosensory receptors which via the medullary swallowing centre triggers a reflex closure of the upper oesophageal sphincter.
2. Pharyngeal phase - Involuntary
   Propels food from pharynx into esophagus. Soft palate is raised to stop the bolus entering the nasopharynx. Epiglottis contracts to block larynx and prevent aspiration into the trachea. Upper esophageal sphincter opens and allow food to enter the esophagus.
3. Esophageal Phase - Involuntary
   Bolus is propelled from the pharynx into the esophagus.
   Upper esophageal sphincter contracts to prevent reflux. A primary peristaltic wave propels the food bolus from the esophagus into the stomach. If this is not effective a secondary peristaltic wave can be initiated to clear the food.

Question 18

Neural control of deglutition is controlled from the reticular formation with efferent outputs via?

Answer 18

CN V, VII, IX, X, XII

Question 19

What is dysphagia?

Answer 19

• Medical condition that makes it difficult or painful for a person to swallow.

Question 20

Peristalsis is an intrinsic local reflex. What muscles are contracting/relaxing in this process?

Answer 20

Remember that ACh + Substance P produce contraction at excitatory neurone, whereas NO + VIP produce relaxation at inhibitory neurone

Question 21

Describe the process of peristalsis.

Answer 21

1. Food causes distension and leads to sheer stress of mucosal cells
2. Epithelial cells release 5-HT serotonin
3. Activates Intrinsic Primary Afferent Neuron (IPAN)

-> Releases ACh at synapse with excitatory motor neuron
1. Excitatory neuron releases ACh and Substance P
2. Causes contraction of CM at oral end

-> Releases ACh/5-HT at inhibitory motor neuron
1. Inhibitory neuron releases NO and vasoactive intestinal peptide (VIP)
2. Causes relaxation of CM at anal end which decreases resistance to downstream movement

Question 22

What is Hirschsprung disease?

Answer 22

• Severe constipation > congenital megacolon
  > Characterized by an absence of the ENS in the distal colon (no migration of neurons of the myenteric plexus into rectum).
  > The involved segment exhibits increased tone, has a very narrow lumen, and is devoid of propulsive activity.
  > As a result, the colon proximal to the diseased segment becomes dilated, thus producing a megacolon.
• This condition is treated through surgical removal of the diseased segment.

Question 23

Slow wave frequency varies through the GI tract:
Small intestine - 10 to 20 times/minute
Stomach & large intestine - 3 to 8 times/minute

• What are slow waves and how are they generated?

Answer 23

• Cyclical changes in membrane potential on GIT smooth muscle
• Waves of partial depolarization in smooth muscle sweep along the digestive tube for long distances
• Resting membrane potential = -50/-60 BUT spontaneous fluctuations by 5/15mv spread to adjacent sections of smooth muscle, giving rise to the “slow waves.”
• Prepare the smooth muscle cells contractions by controlling the appearance of “spike potentials,” which are a type of depolarisation event that can lead to muscle contractions. Slow waves set the basic rhythm of smooth muscle contractions.

-> Generated by pacemaker cells - Interstitial cells of Cajal (ICC)

Question 24

How do we get from the bolus distending the gut and stretching walls to contraction?

Answer 24

-COORDINATED MUSCLE CONTRACTIONS

Question 25

What is the role of ICC cells in contraction?

Answer 25

- Interstitial cells of Cajal (ICC) produce cyclic slow waves caused by Ca2+ channels opening (depolarisation) and K+ channels opening (repolarisation) - They do not directly lead to contraction! an action potential needs to be generated by reaching threshold - Depolarisation leads to hypopolarised state in smooth muscle cells which increases the likelihood of reaching threshold → opening of L type VG Ca2+ channels → ACTION POTENTIAL = CONTRACTION

Question 26

How can slow waves be modulated by other inputs to trigger contractions?

Answer 26

- The modulation of slow waves in the GI tract involves the integration of various inputs, including neural, hormonal, mechanical, and chemical factors. These inputs can influence the activity of ICCs and smooth muscle cells, adjusting the timing and strength of contractions to optimize the digestive process. > Tonic (continuous) slow waves + ANS or endocrine input = Phasic (in phases) contraction

Question 27

What is the migrating motor complex?

Answer 27

- Cycle of **electrical activity** triggering **motor activity** that occurs in the **fasting state.** - **Clears and cleanses the stomach contents** before the next meal.

Question 28

Describe the process of the Migrating motor complex.

Answer 28

- ENS signals initiate onset of MMC (fasting) -> Phase 1: Quiescence GIT tract has minimal or no contractile activity.= resting period before the initiation of the MMC cycle -> Phase 2: Phase II: Initiation Activation of the ENS leads to the onset of irregular, Low amplitude contractions. (Gradually increase in frequency & amplitude, preparing for the upcoming active phase.) -> Phase III: Active phase Characterized by Intense coordinated contractions. Stomach → terminal ileum. = Propel luminal contents forward, clearing out residual material, bacteria, and debris. * Thought to be elicited by **motilin** – amino acid peptide released from M cells in the duodenum.

Question 29

What is Achalasia + Causes? Treatment?

Answer 29

- A failure of esophageal peristalsis and relaxation of the lower esophageal sphincter in response to swallowing. > Caused by the loss of the VIP and nitric oxide-releasing inhibitory interneurons in the myenteric plexus. Excitatory neural tone dominates preventing LES relaxation. * Possibly an autoimmune disease as activated cytotoxic T-cell infiltration has been observed in patients, as well as antibodies to myenteric neurons. Heller myotomy, botulinum toxin & endoscopic pneumatic dilatation.

Question 30

What is the gastric accommodation reflex? What is its function?

Answer 30

- Reflex that allows stomach to **relax and increase compliance** to accommodate food volume. - Mediated by **vagovagal reflex pathway** that activates inhibitory motor neurons in the gastric wall to release nitric oxide and vasoactive intestinal polypeptide VIP FUNCTIONS: 1- Prevents pressure rising in the stomach 2- Provides time to allow efficient mixing & breakdown of food & controlled release of chyme into the duodenum 3- Allows stomach to be a temporary food store

Question 31

Explain the process of the gastric accommodation reflex.

Answer 31

Question 32

Describe how we get churning in the stomach.

Answer 32

1- Slow waves generate peristaltic contractions starting in body → antrum (propels food to antrum & pyloric sphincter) 2- At pylorus, the slow wave triggers pyloric sphincter contraction –preventing chyme release into duodenum >A stronger wave follows behind which helps grind food up against itself into smaller pieces 3- Increased pressure in antrum pushes stomach contents back towards body (called retropulsion) → grinding motion to break up large food particles → creates liquid chyme to release into the duodenum 4- Liquid chyme slowly released in resting phases between contractions > Particles <2mm pass through pyloric sphincter > Remaining large particles cleared by MMC

Question 33

What is Gastroparesis? - Symptoms - Causes? - What condition is it a serious complication?

Answer 33

- Delayed gastric emptying in the absence of a blockage in the stomach. > Failure of normal physiological motility patterns. - Early satiety, bloating, nausea and vomiting. - Often caused by vagal injury - leading to reduced strength of stomach contraction and failure of the pyloric sphincter to effectively relax. - Gastroparesis is a serious complication seen in diabetics as hyperglycaemia damages both the vagus nerve, preventing the vagovagal reflex, and the interstial cells of cajal .

Question 34

What is emesis?

Answer 34

Vommiting: Defensive mechanism to remove potentially harmful substances in the GI tract before damage - Activation of emetic coordinating circuitry in the medulla oblongata.

Question 35

What role do the: - Vomiting centre - Area Postrema - Nucleus of the solitary tract have in emesis?

Answer 35

- Vomiting centre (VC), in the medulla oblongata, is the main site of neural control of vomiting. = receives signals from other centres (e.g. CTZ) & coordinates output - The area postrema (anti-emetic target) includes a chemoreceptor trigger zone (CTZ) (outside BBB), which allow chemical changes in bloodstream to induce feelings of nausea & triggers vomiting - Nucleus of the solitary tract plays critical role in the initiation & integration of a wide variety of reflexes (e.g. GIT motility)

Question 36

Describe the process of emesis.

Answer 36

1- Wave of reverse peristalsis (coordinated by nucleus tractus soltaris) beginning in the distal small intestine moves intestinal contents orally. - Skeletal muscle groups are also triggered to contract to **decrease thoracic pressure** and **increase abdominal pressure** to help propel the contents out of the stomach. - The autonomic centres regulating sweating, lacrimation, salivation and heart rate all lie close to the VC, and these autonomic phenomena are all stimulated in the surge of neuronal activity that accompanies vomiting.

Question 37

Describe the 3 phases of emesis.

Answer 37

Question 38

What is segmentation? What brings them about?

Answer 38

- Segmentation plays a role in mixing the contents of the small & large intestines. - Different regions of the circular muscle of the gut contract to pinch off lengths of gut contents. - As one set of contractions end, the next begins but with contractions in different places. This helps mix the contents of the GI tract with digestive secretions and bring them into close contact with the mucosa. *Elicited by slow waves – a series of waves creates phasic contractions that allow these pinching events to occur at relatively regular intervals

Question 39

How would you describe peristalsis in the Colon?

Answer 39

Peristalsis is sluggish in the colon. Poor motility leads to greater water and electrolyte reabsorption – but potentially leading to constipation

Question 40

What is haustration of the colon?

Answer 40

- Mixing - Like segmentation but larger segments - Motor events in proximal colon - Contractions of circular muscles create pockets (haustra)

Question 41

What is mass movement of the colon? What triggers this?

Answer 41

- Propulsion - Enhanced rate of peristalsis - Motor events in distal colon - Strong contractions preceded by disappearance of haustra and relaxation of circular muscle to facilitate rapid movement of colonic contents for up to 30 minutes Gastrocolic and duodenocolic reflexes trigger mass movements – triggers faster peristalsis to help empty colon to accommodate new food