EXAMples

Question 1

Ga/i coupled examples

Answer 1

• A2 Adrenoreceptors in the smooth muscle
• Opoid receptors in the myenteric plexus
• Neuropeptide Y receptor on vagal afferents as part of the gut brain axis
• SS2 receptor, somatostatin binding has inhibitory effects particularly on acid secretion.

Question 2

G a/s coupled examples

Answer 2

• Gastric inhibibitory polypeptide receptor ; inhibits gastrin release
• GLP-1; promotes insulin synthesis and release
• H2 receptors on parietal cells, H2 binding increases intracellular cAMP and gastric acid release.
• TGR5, bile acid receptor

Question 3

Gq coupled receptors

Answer 3

M3 Receptor;

A1 receptor; vasoconstriction

B2 receptor; vasoconstriction of sphincter muscles

CCK2 receptors, gastrin binding increases release of histamine from ECL cells, gall bladder contraction, pancreatic secretion

Question 4

Type 2 nuclear receptors

Answer 4

FXR receptor; in the intestine increases transcription of bile acid transporter whereas in the liver decreases expression of target genes which are responsible for bile acid synthesis. Epigenetic changes in the DNA allow for different outcomes even though the same receptor is being activated.

Exists a homodimer with RXR bound to corepressor proteins, ligand binding displaces corepressors and recruits coactivators. TM activated !

Question 5

Type 1 nuclear receptors

Answer 5

Glucocorticoid receptors - Used as treatment for IBD, ligand receptor complexation results in unbinding of molecular chaperones from the AF2 domain, exposition of the dimerisation sequence and synergizing of AF1 and AF2 domains. Dimerisation occurs and homo-dimer translocates to the nucleus. Complex will bind to HRE, either activating TM or bind to the HRE displacing a TF and thus deactivating TM. OUTCOMES: decreased collagen deposition, release of anti inflammatory mediators (IL10) Metabolic effects include decreased glucose uptake and utilisation

Glucocorticoids are released when cholesterol is high

Question 6

Emesis/ nausea

Answer 6

Vomiting is regulated by the emetic centre located in the medulla oblongata, this is not dso much a specific area but a more a region of integrated neural circuitry receiving input from higher cortical areas, other brain regions such as the amygdala and balance centre and also the chemoreceptor trigger zone located in the area prostema . Sensory information run via vagal afferents to the CTZ from the stomach, triggers for emesis include excessive stretch of the intestine or stomach and chemical triggers sensed by enterochromaffin cells (i.e. irritation to the mucosa or presence of toxins within the lumen). The CTZ is outside of the blood brain barrier so toxins in the blood can also trigger emesis. The main neurotransmitters involved in this process are ACh, histamine, substance P and 5HT. Vomiting is preceded by increase in salivation, heavy breathing and pallor. At the moment of vomiting the mastication centre will close the epiglottis and elevate the soft pallet. Strong parasympathetic cholinergic innervation of the enteric nervous system and directly onto effector smooth muscle will result in forceful contractions and sphincter relaxation resulting in the ejection of the contents of the stomach.

Scopolamine: M3 receptor antagonist
5 HT3 receptor antagonists: i.e. Granisetron, most common site of action is CTZ.
D2 (Gi) antagonists: Chloropromazine(CTZ), Metoclopramide (CTZ and peripheral action on the GIT itself to increase rae of gastric emptying.

Question 7

Constipation

Answer 7

Caused by a decrease in gastric motility, often seen in the elderly or caused by damage or disruption to the function of the enteric nervous system.

Laxatives: work in one way or another to increase osmolarity in the lumen increasing water secretion and producing stretch in the colon which is itself a trigger for motility and defecation.

Question 8

Diarrhoea

Answer 8

During diarrhea there is an increase in GIT motility, accompanied by either an increase in water secretion or decrease in water absorption.

Opioids i.e. loperamide: Opioid receptors are Gs coupled, ligand receptor coupling thus results in inhibition of adenylate cyclase, and opening of K+ and Ca2+ channels. In high concentrations there is also evidence to suggest that opioid receptors may inhibit the action on calmodulin.

Question 9

CFTR mutations

Answer 9

Class 1 is the most severe phenotype as no synthesis of full length normal CFTR protein is produced, due to nonsense mutations, frameshift mutations or aberrant splicing of mRNA. These mutations prevent the synthesis of a stable protein or result in a truncated protein due to the presence of an immature termination codon. 
Class 2  Protein Maturation: In class 2 mutations three adjacent nucleotides are deleted in the transcript coding for the second nucleotide binding domain, leading to the misfolding of the protein. Due to this the protein is not recognized by molecular chaperones and therefore mislocalized
Class 3: Dysfunctional gating mechanism: In mutations of this type the CFTR protein is successfully produced and localized to the cell membrane, however, is unable to respond to cAMP stimulation. 
Class 4: Mutation effecting CL- conductance: Protein is correctly translocated to the cell and responds to stimulus but conducts an attenuated CL- current, mutations of this type are found in the membrane spanning domain. 
Class 5: Mutations effecting protein stability:  In this mutation, the last 70-90 amino acids of the C- terminus are missing. While these amino acid residues play

Question 10

Chloera

Answer 10

The cholera toxin catalyses a conjugate reaction (ADP ribosylation) on the alpha subunit of a g protein resulting in its persistent activation. The continual increase of cAMP concentration and resultant pKA activation leads to the constant phosphorylation of the regulatory domain of the CFTR channel and hence its activation. This leads to continual flow of chloride ions out of the epithelium and into the luminal environment, a reversal of the homeostatic osmotic gradients and therefore severe diarrhoea and dehydration