Drug-Receptor Interactions

Question 1

5 major types of cell receptors

Answer 1

Intracellular
Ligand-gated transmembrane proteins
Cytokine receptor mechanism
Ligand-gated ion channels
G-protein family of transmembrane receptors

Question 2

Cellular membrane components of a ligand-regulated transmembrane enzyme

Answer 2

Cytoplasmic hormone binding domain (TK, SK, or guanalyl cyclase), EC hormone binding domain.

Question 3

What prolongs the activation of a ligand-regulated transmembrane enzyme?

Answer 3

Autophosphorylation of tyrosine residues

Question 4

Cytokine receptor mechanisms

Answer 4

Closely resembles tyrosine kinase but utilizes a separate protein tyrosine kinase that binds non-covalently to the membrane

Question 5

Ligand-gated channel receptors - membrane components

Answer 5

Pentamer: 2 alpha subunits, then beta, delta, and gamma. Drug binds to an alpha subunit.

Question 6

Common example of a ligand-gated channel receptor

Answer 6

Nicotinic cholinergic receptor

Question 7

Membrane structure in G-protein coupled receptor

Answer 7

Polypeptide that spans the membrane 7 times, with amino group on the extracellular side and carboxy group in the cytoplasm

Question 8

Steps involved in the adenylyl cyclase pathway

Answer 8

1. Agonist binds and ternary complex forms
2. Ternary complex binds GTP rather than GDP
3. GTP and alpha subunit dissociate from beta-gamma
4. Alpha subunit stimulates breakdown of ATP into cAMP and activates PKA. cAMP and PKA have downstream targets.
5. Alpha subunit remains active until the GTPase converts GTP back to GDP.
6. Non-active alpha subunit with bound GDP reforms the ternary complex

Question 9

Describe the steps involved in receptor signaling via the phospholipase C pathway

Answer 9

1. Agonist binds and ternary complex forms
2. Ternary complex binds GTP rather than GDP
3. GTP and alpha subunit dissociate from beta-gamma
4. Alpha subunit stimulates PLC, which will facilitate breakdown of PIP2 into IP3 and DAG. IP3 stimulates release of intracellular calcium from the ER, activating calmodulin. DAG activates PKC.
5. Alpha subunit remains active until the GTPase converts GTP back to GDP.
6. Non-active alpha subunit with bound GDP reforms the ternary complex

Question 10

Three ways by which drugs can produce beneficial vs toxic

Answer 10

Actions at the same receptor, producing direct extension of the drug
Actions at the same receptors at different tissues
Actions by different types of receptors

Question 11

Idiosyncratic drug response

Answer 11

Unusual response that is not frequently observed in the majority of patients

Question 12

Tachyphylaxis

Answer 12

Rapid development of diminished responsiveness after administration of a drug

Question 13

Pharmacodynamic tolerance - different methods

Answer 13

Binding of beta-arrestin
Loss of membrane-bound receptors
Uncoupling from post-receptor moieties from functional modification of G-proteins and/or subsequent second messenger enzymes

Question 14

Mechanism of homologous desensitization

Answer 14

GRK2 and GRK3 functionally uncouple receptors and trigger sequestration from the cell

Question 15

Mechanism of heterologous desensitization

Answer 15

Several protein kinases promote phosphorylation of receptors, PKA, and PKC. This functionally uncouples receptors and impairs interactions with G-proteins

Question 16

Supersensitivity

Answer 16

Compensatory mechanism from the loss of hormonal activity on receptors leading to increase in the number of receptors and/or enhanced receptor-effector coupling.