PHS233 GI Motility Lecture 2024 PDF

Compare and contrast general regulation of the GI tract by the ENS, the CNS, and hormones. Consider the duration of the response and the advantages and disadvantages of each. We will go over some answers briefly at the start of the next lecture. Note: while there are no...

Compare and contrast general regulation of the GI tract by the ENS, the CNS, and hormones. Consider the duration of the response and the advantages and disadvantages of each. We will go over some answers briefly at the start of the next lecture. Note: while there are no mini essays for 233 this year, writing this type of mini essay is a good way to revise a lecture.  Compare and contrast general regulation of the GI tract by the ENS, the CNS, and hormones. Speed and Can it act Distance regulation Number of sites of Stimulus for Control signals / duration of independently of Advantages can occur over action response Signal molecules response other systems Very local, Intrinsic - chemo Neural / action Fast local Yes – ENS is generally only Fast and short / osmo / mechano potentials responses to ENS Very short (cm) sometimes called the effectors within one duration receptors within the Neurotransmitter conditions within a brain of the gut organ GI tract NOS- inhibits regon of the GI tract Neural / AP’s Neurotransmitter s Extrinsic - Special Coordinates fast and Parasympathetic senses, emotional No, only ENS directly Fast coordination of Long distances (Via complex actions / Ach - stimulates Fast and short responses. inervates GI tract compex movements of CNS the autonomic involving several sites Sympathetic/ duration Long reflex pathway - structures so must act short duration over nervous system) of action (e.g. adrenaline- receptors within via the ENS long distances swallowing) inhibits. 2ndary the GI tract neurotransmitter in ENS Enteroendocrine cells Yes – some >apical receptors -> hormones released Cause release of Slow but sustained Each hormone Stimuli include both Slow and from the GI tract in peptide hormone. coordinated response regulates more than the GI tract luminal Hormones Long distances sustained response to GI Endocrine (Blood) over long distances / one cell type in more content and external / duration tract luminal Paracrine local several organs of the than one organ extrinsic stimuli conditions act on the (diffusion) GI tract GI tract. Neurocrine (interacts with NS) Phasic vs Tonic contractions 01 02  WHAT IS IT? Starts 4-5 hours post meal absorption Duration – stomach to the end of the large intestine, 2 hours 3 phases - intense, inactive, intermittent, coordinated in stomach then small intestine FUNCTION AND REGULATION Functions: Clears undigested material & secretions Regulates intestinal microflora Epithelial cell turnover Regulation: Hormonal - Motilin released by intestinal m-cells directly modulates muscle Neuronal -Motilin also stimulates both the enteric and autonomic NS (neurocrine effect) Which of the following is a function of the fasting Migrating Motor Complex (MMC) in the stomach? 1. Contraction of the pyloric sphincter. 2. Clearing residual secretions. 3. Stimulation of HCl secretion. 4. Initiation of defecation.  WHAT IS IT? Relaxation of smooth muscle allows the volume of luminal contents to increase without change in pressure. Occurs in the stomach and the colon. EXAMPLES IN THE STOMACH 1. Receptive relaxation Swallowing triggers reduced muscle tone as food is moved down the esophagus. Allows food to enter the stomach without a change in pressure in the stomach.. Prevents gastric reflux in the stomach 2. Accommodation Progressive relaxation in response to a volume change / stretch.  WHAT IS IT? Motility patterns that move or propel chyme / food through the GI tract. Occurs in the oesophagus, stomach, small intestine and large intestine Combines with other motility to produce complex patterns (e.g. retropulsion which has a mixing function) EXAMPLE PERISTELSIS Ascending circular muscle contraction behind bolus. Descending circular muscle relaxation ahead of bolus. Longitudinal muscle shortening (contraction) to reduce the distance the food / chyme needs to be pushed  WHAT IS IT? Motility patterns that mix chyme with enzymes and other secretions and expose chyme to absorptive surfaces. In the stomach mixing (retropulsion) also contributes to mechanical digestion but this is complete by the time chyme gets released to the smll intestine. EXAMPLE SEGMENTATION Circular muscle contraction in alternating segments causing the chyme to be moved back and forth in the intestinal tube. Which of the following statements about the spontaneous contractions of intestinal smooth muscle is correct? 1. Spread of spontaneous contractions depends on adherans junctions between intestinal smooth muscle cells. 2. The frequency of contractions is dependent on autonomic regulation. 3. The amplitude is decreased by the parasympathetic nervous system. 4. They are phasic contractions generated by interstitial cells of Cajal. The surprisingly charming science of your gut | Giulia Enders https://www.youtube.com/watch?v=BJ-C99FwRHQ MULTI- UNIT E.g. Vascular smooth muscle Individual muscle cells contract independently UNITARY GI Tract smooth muscle Act as a syncytium (cells contract together) WHY DO UNITARY MUSCLE CELLS CONTRACT TOGETHER? Extensive intercellular communication Cells electrically connected via gap junctions. Cells physically connected via adherens junctions WHAT REGULATES UNITARY SMOOTH MUSCLE? Hormones and ENS neurons Circular and longitudinal muscle layers are arranged with a neural plexus between them (myenteric plexus) The image shows superimposed images of circular (lower layer) and longitudinal (above) intestinal smooth muscle sandwiching neural components of the myenteric plexus – shown by Asterix. WHAT ARE THE UNITARY SMOOTH MUSCLE CELLS LIKE? Cells are 5 – 20 µM diameter and ~ 500 µM long Contain actin and myosin filaments Individual muscles interact with ~10 surrounding cells via gap junctions and adherens junctions Irregular arrangement – not striated as in SKM WHAT DO INTERSTITIAL CELLS OF CAJAL (ICC) DO? Generate slow waves - membrane potential varies between -40 and -80 mV. Thus, function as pace makers. Rhythmic changes in the activity of Na+/K+-ATPase & membrane K+ conductance Electrically linked to other ICC & muscle cells by gap junctions multiple branching processes projecting to surrounding smooth muscle cells WHERE ARE THEY LOCATED? Stomach and small intestine In the smooth muscle layer close to myenteric plexus Colon In the boundary between muscle layer and submucosal layer. RELATIONSHIP BETWEEN SLOW WAVES AND GI TRACT CONTRACTIONS. Frequency of slow waves is a property of the ICC in each region. Faster in the proximal regions of the GI tract (digestion), e.g. Duodenum 12 – 20 per minute. Slower in the distal regions of the GI tract (absorption), e.g. Colon 6-8 per minute. ACTION POTENTIALS DETERMINE THE SIZE OF THE CONTRACTION If the membrane potential does not reach threshold no contraction. The longer the potential is above threshold, the more APs, the bigger the contraction Source: http://getdrawings.com/search/smooth%20muscle  Increased cytosolic Ca2+ Ca2+ binds to calmodulin Ca2+ /calmodulin complex activates myosin light chain (MLCK) MLCK uses ATP to phosphorylate myosin Actin and myosin interact and cross bridge cycles produce tension ACTION POTENTIALS DETERMINE FORCE (AMPLITUDE) OF CONTRACTION Little or no contraction occurs in absence of action potentials If the membrane potential does not reach threshold no contraction. Greater the number of action potentials the greater the force of contraction The longer the potential is above threshold, the more APs, the bigger the contraction. CALCIUM ALSO CONTRIBUTES Elevated Ca2+ means more calmodulin / MLCK activation. Up-regulation Mechanism 1 – Depolarisation of the cell membrane. This opens voltage gated Na+ and Ca2+ channels in sarcolemma (cell membrane) Results in an Influx of Ca2+ which: Activates the ryanodine receptor resulting in release of Ca2+ from the sarcoplasmic reticulum (Ca2+ induced Ca2+ release) Activates contraction (calmodulin & MLCK) This increases the magnitude of contractions Up-regulation Mechanism 2 – Pharmomechanical Contraction Hormones & neurotransmitters bind to a receptor to induce Ca2+ release. Gαq - Signaling pathway activated Receptor activation of phospholipase C Production of IP3 IP3 induces release of Ca2+ from sarcoplasmic reticulum This increases the magnitude of contractions Down-regulation of Phasic Contractions – 3 signals contribute 1. Hyperpolarisation of smooth muscle cell membrane (or decrease Ca2+) Receptors open ion channels that hyperpolarize cells. Slow waves do not pass threshold - No contraction Or Pass threshold but reduce the number of action potentials to Reduced force 2. Increased activity of Myosin Light Chain Phosphatase Dephosphorylates myosin so the force of contraction is reduced. 3. Inhibition of excitatory ENS neurotransmission Example is opioid drugs. In smooth muscle cells, what must happen to allow actin and myosin to form cross bridges? 1. Myosin light chain kinase phosphorylates myosin 2. Troponin phosphorylates myosin 3. Troponin moves tropomyosin. 4. Myosin light chain kinase moves tropomyosin REGULATION EXAMPLES Relaxation Stress Opioid drugs  Overview of regulation Hormones and neurotransmitters regulate magnitude/strength of contraction only Little effect on frequency (this is determined by ICC and varies by region) Mechanisms Modulate the membrane potential or Ca2+ To increase: Depolarize or increase Ca2+ To decrease: Hyperpolarize or decrease Ca2+ Increasing the amount of Myosin Light Chain Phosphatase will de-phosphorylate myosin and reduce cross bridge cycling. Blocking excitatory neurotransmission will decrease contractions.  Example Stress Mechanisms Stress is detected by the CNS (think senses that can see / hear / smell / feel stressful stimuli) CNS sends a message to the ENS via the sympathetic NS which uses adrenaline as a neurotransmitter. ENS has α adrenergic receptors ENS sends inhibitory signal to smooth muscles (uses different inhibitory neurotransmitters to the CNS e.g. Nitrous oxide) To decrease size of contraction: NO increases the amount of Myosin light chain Phosphatase de-phosphorylates myosin and reduce cross bridge cycling.  Example Relaxation Mechanisms That you are in a safe space is detected by the CNS (think senses that can see / hear / smell / feel relaxing stimuli) CNS sends a message to the ENS via the parasympathetic NS which uses acetylcholine as a neurotransmitter. ENS has muscarinic cholinergic receptors ENS sends excitatory signal to smooth muscles also using ach. To increase size of contraction: Depolarize or increase Ca2+  Example Opioid drugs Mechanism - Inhibition of excitatory ENS neurotransmission Opioids bind to opioid receptors in the myenteric plexus. These are Gαi receptors which inhibit neurotransmission by ENS neurons. Excitatory signals are blocked and don’t get to the GI smooth muscle. On the day he died, Elvis was found in an unresponsive state on his bathroom (toilet) floor, he could not be resuscitated. Case study Autopsy findings include: Did a History of opioid drug use problem with GI Constipation and enlarged colon Heart disease / enlarged heart Cardiac arrest / heart attack as a probable cause of death. tract FREQUENT AND motility kill Elvis? MYENTERIC REDUCED GI CONSTIPATION STRONG USE OF THE PLEXUS MUSCLE + VALSALVA INHIBITED BY CONTRACTION Enlarged colon MANEUVER TO OPIOIDS INCREASE Mechanism of action for opioid drugs - FORCE FOR Inhibition of excitatory ENS ELIMINATION. neurotransmission VALSALVA INCREASED AORTIC MANOEUVRE INTRATHORACIC COMPRESSION HEART PRESSURE + INCREASES ATTACK! AORTIC PRESSURE  Briefly summarise the molecular mechanisms by which phasic contractions are up and down regulated in the GI tract and give an example of each. We will go over some answers briefly at the start of the next lecture and use this as a lecture summary. Note: while there are no mini essays for 233 this year, writing this type of mini essay is a good way to revise a lecture. Brainstorming in a group can be a good way to do this and have fun!.