Study Questions - Drug Receptors

1. Give two examples of receptors that fall into each of the major groups that were discussed (regulatory proteins, enzymes, transport proteins, structural proteins).

Regulatory Proteins – hormones, autocoids, neurotransmitters Enzymes – inhibition and activation (DHFR – dihydrofolate reductase; cyclooxygenase – inhibited by NSAIDs) Transport Proteins – ion channels, gated channels, pumps Structural proteins – tubulin 2. Define agonist, partial agonist, and antagonist. Rank each in terms of potency and efficacy.

Agonist – drug or other chemical that can combine with a receptor on a cell to produce a physiologic reaction typical of a naturally occurring substance Partial Agonist – an agonist whose maximal effect is less than the maximal effect of the tissue (may appear to behave as an antagonist if it is added to a situation previously involving only a full agonist) Antagonist – something that opposes the effect of an agonist usually by blocking the interaction between it and that receptor 3. What is the equation that describes the relationship between Kd and the fraction of total receptors that will be occupied at a given concentration of agonist? What does this equation simplify to when the Kd is equal to the agonist concentration at which 50% of the receptors are occupied by agonist?

4.

What do the terms potency and efficacy tell us about the action of a drug?

Potency is a measure of the drug’s ability to exert a given effect. Efficacy is the evaluation of a drug taking into consideration potency and toxicity (ie. The most potent drug is not always the most efficacious). 5. What is the potential effect on receptor function when the number of receptors in a cell that interact specifically interact with agonist Y are dramatically increased?

This can either increase the maximal response that is possible and/or it could create a situation where spare receptors are prevalent. 6. How does one demonstrate that a cell contains spare receptors for agonist Y?

This can be demonstrated by adding irreversible antagonist in order to decrease the number of receptors available while holding the amount of agonist constant. If the maximal effect is still able to be reached while adding irreversible antagonists, then there were spare receptors. The EC50 increases continuously whether the maximum effect is changing or not.

7.

How can one determine if an antagonist is a competitive antagonist or a noncompetitive antagonist?

If the antagonist is competitive, the maximum response will remain the same but will require more agonist in order to achieve it. If the antagonist added is noncompetitive (irreversible), the maximum response able to be attained will decrease because some of the receptors are no longer available for interaction with the agonist. 8. Describe the mechanism by which HSP 90 modulates the effects of estrogen?

HSP 90 modulates the effects of estrogen by dissociating from the receptor (in turn exposing the DNA binding domain) when estrogen binds. This allows transcription to take place and eventually produce proteins which elicit some sort of effect. 9. Why would there be a lag period prior to seeing the effects of cells which were treated with vitamin D?

Vitamin D is a lipid soluble hormone that acts by triggering synthesis of signal proteins via transcription. The lag period observed is due to the time it takes from stimulation until the signaling molecules are actually synthesized. 10. How would a drug which blocked receptor internalization alter the ability of the cell to regulate receptor number?

The ability to down regulate would be decreased meaning there would be a constant level of possible stimulation. This means that receptor number would no longer be able to decrease as a result of internalization. 11. Describe the role of JAK in signal transduction involving autocoid receptors.

JAK = janus kinase (separate from the receptor) This kinase phosphorylates the receptor which then allow STAT (signal transducers and activators of transcription) molecules to bind and be phosphorylated by the JAKs which may then dimerize and alter transcription in the nucleus. 12. Describe the role of the intrinsic Gα GTPase, the pseudosubstrate sequence of PKA, and βadrenergic receptor kinase in the function of cAMP as a second messenger.

Gα GTPase is activated by the receptor and in turn activates adenylate cyclase. PKA (protein kinase a) is a cAMP dependent kinase with regulatory subunits. The regulatory subunits have a pseudosubstrate sequence that mimics that of a true substrate allowing it the ability to bind to and block the active site. The regulatory subunits are released only after bound by cAMP. β-adrenergic receptor is the receptor that interacts with the original ligand (and I assume the kinase is an intrinsic enzyme involved in the activation of the G-protein pathway).

13.

What is the role of IP3 in regulating the activation of PKC and calmodulin?

IP3 causes the release of calcium from storage sites. This cytoplasmic calcium can then interact with calmodulin so it can then regulate the activity of calcium-dependent protein kinases. PKC is activated by DAG, a molecule confined to the membrane. PKC acts upon substrates (phosphorylates) that then coordinate action with the calmodulin side of the pathway to create some sort of response. 14. Describe the difference between homologous and heterologous desensitization.

Homologous desensitization – negative feedback is directed at the level of receptor, which is then regulated by some mechanism (phosphorylation, decreased synthesis, internalization)ex. B-arrestin Heterologous desensitization – negative feedback directed at downstream signaling molecules 15. When considering the effects of a drug which is likely to be prescribed to a large population of patients, what information can be gained from quantal dose-effect curves?

ED50 – dose required to elicit desired effect in 50% of the test population TD50 – dose required to be toxic in half of subjects LD50 – dose required to kill half of subjects Therapeutic Index 16. Describe how the therapeutic index for a drug is determined.

LD50/ED50 = therapeutic index (higher index is better because it is safer – ideally, lethality requires very high dose while effectiveness requires low dose) This indicates a large gap between the lethal dose and the effective dose for the 50th percentile. This typically means that the therapeutic window is very large. 17. Why is selective a more appropriate term than specific when describing interactions between drugs and receptors?

Selective is used because it is much more likely. It describes a situation where the unwanted drugs are discriminated against (“picky”) oppose to specific, which nearly implies that there is a very specific structure that is desired. 18. What approaches to pharmacotherapy can be taken to minimize toxic effects and maximize the benefits of drugs?

Use the lowest possible does to achieve the desired therapeutic effect in order to avoid toxicity. Combination therapy also decreases the likelihood of toxicity because it allows two different agents with the same indications to be used at relatively lower doses. This only makes sense if the medications elicit different side effects.

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