W3.2_Receptors in GI Tract

Question 1

How does chemical signals give biological effects through receptors?

Answer 1

chemical signal -> signal transduction -> activation or deactivation of effector protein -> signalling pathway -> biological effect

Question 2

What can a drug target be? Where would it be? Explain how drug compounds can bind to ligand by relating to superfamilies of receptors and their diversity.

Answer 2

• Target: usually a protein (enzyme/receptor)/DNA/RNA/small chemical mediators in blood
• Often in cell membrane, but can be nuclear/cytoplasmic (inside cell)
• Drug compound has complementary structure to ligand in order to bind
• Each superfamily of receptors follow a specific molecular organisation and signal transduction mechanism
• Diversity in each superfamily from sequence variations and different in lengths of extracellular and intracellular domains, having different pharmacological properties

Question 3

Describe the properties of a ligand gated ion channel (3). How does a drug molecule triggers a neurotransmitting response through the channel.

Answer 3

• Membrane spanning, multiple subunits (pentameric/tetrameric/trimeric) form a pore/channel, binding site on extracellular site
• Ligand binds to receptor -> conformational change of receptor that opens the pore -> selected ions enter the pore and usually move from outside to inside of cell (passive movement driven by electrochemical gradient of permeant ions) -> increased cation entry (Na+/Ca2+) triggers neurotransmitter release/action potential

Question 4

Describe the properties of a G-protein coupled receptor (GPCR) (2). What section/compounds bind to the exterior/interior section of the receptor?

Answer 4

• Has 7 very lipophilic membrane-spanning regions/domains, each receptor has its own extracellular domain and G-protein binding site
• Ligand binds to exterior section of receptor, interior section linked to G-protein

Question 5

What are the properties of G-protein? Describe the general biological response pathway of GPCR.

Answer 5

• G-protein is trimeric (αβγ), with different types of α subunit
• Ligand binds to receptor -> GDP associated with α subunit is exchanged for GTP to activate α -> βγ subunits dissociate from α subunit -> cellular response triggered by α or βγ -> hydrolysis of GTP to GDP terminates the signal -> goes back to resting phase

Question 6

Describe the response pathway of G(αs)-GTP. How can the reaction be stopped? Give examples of G(αs)-GTP.

Answer 6

• G(αs)-GTP activates adenylyl cyclase -> produce cAMP -> activates protein kinase A -> protein phosphorylation/change in Ca2+ concentration -> biological response
• Ways to stop the reaction of G(αs)-GTP: protein dephosphorylated by phosphatase or further metabolism of cAMP to 5’-AMP by phosphodiesterase
• Example of G(αs)-GTP: histamine H2 receptors (constitutively active -> basal level of cAMP produced, H2 antagonists actually act as inverse agonists)

Question 7

Describe the response pathway of G(αi)-/G(o)-GTP. Explain the difference in response between μ/δ and κ opioid receptors.

Answer 7

• G(αi)-GTP/G(o)-GTP inhibits adenylyl cyclase (ex. opioid receptors in GI tract present on enteric circuitry that regulates motility and secretion in GI tract)
• In μ/δ opioid receptors: αi inhibits adenylate cyclase -> decreased cAMP and PKA activity + βγ activate K+ channels to cause membrane hyperpolarization and inhibit Ca2+ channels to decrease neurotransmitter release
• In κ opioid receptors: βγ inhibit Ca2+ channels to decrease neurotransmitter release

Question 8

Describe the response pathway of G(q)-GTP.

Answer 8

• G(q)-GTP activates phospholipase C (PLC) -> more conversion of phosphatidylinositol bisphosphate into inositol trisphosphate (IP3) (change Ca2+ concentration) and diacylglycerol (DAG) (activate protein kinase C and cause protein phosphorylation) -> biological response

Question 9

Describe the response pathway of tyrosine kinase receptors. Give out examples of drugs that are related to them.

Answer 9

• Ligands bind to the receptors -> α-helix in membrane and receptor tyrosine kinase proteins bind to form a dimer -> hydrolysis of ATP into ADP activate the tyrosine kinase receptors -> inactive relay proteins are activated by binding the phosphorylated tyrosine -> different tyrosine can activate different proteins and produce different/same biological response
• ex. insulin receptors, growth factors

Question 10

Describe the response pathway of nuclear receptors.

Answer 10

• Receptors in cytoplasm, so drug has to get into the cell
• Drug binds to receptor -> translocates through cytoplasm as a complex into nucleus -> binds to a DNA element to cause increase in transcription of proteins (ex. corticosteroids, hormones)

Question 11

Compare the speed of causing drug toxicity in different types of receptors. Define side effect, adverse effect, and toxicity.

Answer 11

• Speed of receptors varies (milliseconds for ligand-gated ion channels, seconds for GPCRs, minutes/hours for kinase-linked receptors, hours/days for nuclear receptors)
• Side effect: undesired effect that occurs regardless of dose
• Adverse effect: unexpected undesirable effect
• Toxicity: damaging effect that happens at high doses (above therapeutic window)