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Receptor Review
Review of Receptors, Dose Response Relationships
| Question | Answer |
|---|---|
| What do statins target? | inhibit HMG-CoA reductase(for cholesterol metabolism) |
| What enzyme does vancomycin target? | peptidyglycan synthase for cell wall synthesis (antibiotic) |
| * What are the (5) typical drug targets? | CELL SIGNALING RECEPTORS, enzymes, Transport proteins, structural proteins (e.g. macromolecular complexes and cytoskeleton), and nucleic acids |
| What do cardiac digitalis glycosides (e.g. digoxin) target? | Inhibit Na+/K+ ATPase (for heart failure) |
| What does Gentamicin target? | ribosomal protein (aminoglycoside antibiotic) |
| What does taxol target? | Binds to tubulin and promotes microtubule stabilization |
| What does cisplatin target? | Forms adducts with DNA |
| * Why is combined drug therapy necessary (3 main reasons)? | Each drug exhibits non-overlapping toxicities; different mechanisms of action; and different mechanisms of resistance |
| Cellular components that interact with other molecules in a specific and saturable fashion (typically proteins or protein complexes) | What is a Receptor? |
| An ion, molecule, or molecular group that binds to another chemical entity to form a larger complex | What is a Ligand? |
| Where are receptors typically located? | Can be either inside the cell (e.g. steroid hormone receptors) or on the membrane (e.g. insulin receptor) |
| * What is the difference between muscarinic and nicotinic acetylcholine receptors? | Natural ligand is identical for both, but ligands (and antagonists) specific for each subtype exist. Also, different signal transduction system (muscarinic use G-protein, nicotinic use ligant(Na+)-gated ion channels) |
| What does atropine inhibit? | Muscarinic AcR |
| What does alpha-bungarotoxin inhibit? | Nicotinic AcR |
| * How are receptors classified? | Ligand (general and specific), genetic subtype/isoform, downstream coupling, and tissue/cellular distribution |
| What is a genetic subtype/isoform of a receptor? | Alternate form of the same receptor that is no very selective for endogenous ligands (designation is often arbitrary) |
| What is an orphan receptor? | Receptor that is related to other receptors via DNA sequence homology but that has no known ligand (though they may still have downstream effectors and transducers |
| What is downstream coupling? | Some receptor subtypes within a given class can couple to different downstream effectors or transducers |
| What do M1 and M3 AcRs couple to? What about M2 and M4 AcRs? | Gq; Gi |
| * What parameters are receptors classes grouped by? | Ligand specificity, downstream signaling pathways, and DNA sequence homology (among many others) |
| How do ligand-gated ion channels work? | Receptor activation leads to changes in membrane potential due to movement of ions through a channel. Typically quick and short (miliseconds) |
| What type of receptor is Nicotinic AcR? | Ligand-gated ion channel (Na+) |
| What type of receptors are gamma-aminobutyric acid receptors? | GABA receptors are ligand gated ion channels (Cl-) |
| How do benzodiazapines work? | Enhance GABA receptors (increase Cl- flow) |
| Receptors for steroid hormones, thyroid hormones, and retinoids are members of what family of receptor family? | Transcription factors (i.e. nuclear hormone receptor superfamily) |
| How do nuclear hormone receptors work? | Activation modulates DNA binding and transcriptional regulatory properties |
| Members of this class of receptor family typically activated by polypeptide ligands and have a single transmembrane domain. | Receptors are enzymes |
| In this family of receptors, either receptor encoded [e.g. insulin receptor, growth factor receptors] or associated [cytokine receptors] | Tyrosine kinases |
| In this family of receptors, ligands are typically members of the TGF-ß family | Serine/theronine kinases |
| In this family of receptors, receptors function in axonal guidance in nervous system using cell adhesion molecules as ligands | Protein thyrosine phosphatases |
| Activation of this receptor triggers production of second messenger cGMP from GTP (e.g. receptor for atrial natriuretic peptide – functions mainly to regulate blood volume and blood pressure | Guanylyl cyclase |
| These receptors contain seven membrane spanning domains and couple to trimeric G proteins. They are a large family (200-250 members) that responds to a diverse array of ligands (i.e. peptide hormones, biogenic amines, odorants, photons). | G-protein coupled receptors |
| What are the basic assumptions (4) for AJ Clark's receptor theory? | Interaction between ligand (L) and receptor (R) is reversible; all receptors for a given ligand are equivalent and independent; response is directly proportional to number of occupied receptors; ligand exists in only two states: free or receptor-bound. |
| In AJ Clark's receptor theory, what does it mean for ligands to be equivalent and independent? | All receptors for a given ligand are equivalent (they have the same affinity for the ligand) and independent (their affinity remains unchanged upon additional saturation of receptors). |
| What is the chemical equation that Clark's model assumes can describe all receptor-ligand interactions? | R + L <--> RL → Response |
| What is K{D}? | The equilibrium dissociation constant of the RL complex; i.e. K{D} = [L][R]/[LR] |
| What is the equation showing the relationship between the number of bound receptors [RL] and ligand concentrations? | [RL] = [R{T}]*[L]/(K{D}+[L]), where R{T} is the total number of receptors (bound and unbound) |
| What is the fractional occupancy of receptors? | f{B} = [RL]/[R{total}] or f{B} = [L]/([L]+K{D}) |
| * * Half-saturation of reversible ligand binding to a receptor is attained at a ligand concentration equal to the ___ ___. | Disassociation constant (i.e. K{D}) |
| * * Saturation increases from almost zero (f{B} = 0.1) to almost maximal (f{B} = 0.9) in about ___ orders of magnitude of the ligand concentration, irrespective of the affinity of the ligand for the receptor | two |
| When can Clark's model be applied to ligand effects on biological responses (3 assumptions)? | Magnitude of the response is proportional to the amount of receptors bound or occupied; the maximum biological response occurs when all receptors are bound; binding of ligand to receptor does not exhibit cooperativity. |
| What is f{E}? When is it at 50%? | The fractional biological effect or response; f{E} = [L]/([L]+K{D}). 50% effect EC{50} when [L] = K{D} |
| * * When is EC{50} = K{D}? | If the magnitude of a biological response to a ligand is directly proportional to the amount of receptors bound, the EC 50 = K D of ligand binding to the receptor |
| When is it appropriate to use EC{50}? | EC50: effective “concentration” that generates 50% of maximal receptor occupancy or in some cases 50% of the maximal biological response; used whenever the concentration of a substance used is precisely known (i.e. in vitro experiment). |
| When is it appropriate to use ED{50}? | ED50: effective “dose” that gives 50% of a maximal biological response; used in vivo treatments where the absolute concentration of the substance given is not known. |
| A plot of receptor occupancy (or biological response) versus ligand concentration exhibits a ___ ____ ____ ____ curve) | gradual dose response hyperbolic |
| Why does the dose response curve increase linearly at low doses but flatten out as dose becomes larger and larger? | Binding (or response) at low concentrations is in direct proportion to dose; at high doses, receptors are saturated |
| How would you find the ED50 value for a drug using a plot of E/Emax vs. log{dose} curve? | It would be the value of the log{dose} at which E/Emax is at 0.5 (50%) |
| How do you construct a quantal dose-response relationship? What would the ED50 tell you in this case? | X-axis: dose of drug; Y-axis: % of population that exhibit a specific response (predetermined level of a graded response); ED50 tells you the dose at which 50% of population shows desired response |
| * * In a dose response curve, what would give the appearance of "spare receptors"? What would the shift look like? | Amplification of signal duration and intensity leads to a “left” shift in dose response curve where both the half-maximal response is attained at [L] < KD and maximum response attained at [L] below that required for complete receptor occupancy |
| * * What physical phenomena account for the left shift seen with "spare receptors"? | Not necessarily spare receptors-->one activated receptor can interact with many effectors or receptor may have longer half-life or additional amplification may be provided by multiple downstream targets |
| What is albuterol used to treat? | It is an adrenergic receptor agonist used to treat asthma and chronic pulmonary obstructive disease due to bronchodialation effects |
| Why does albuterol's dose-response curve shift to the left? | The receptor itself (B2 - selective adrenergic) is only activated for short time, but downstream effector (G-protein) may be activated for 100s of miliseconds |
| What is potency? | A measure of the amount of ligand (drug) needed to produce an effect of a given magnitude. This is typically defined using the EC 50 , the concentration of ligand or drug required to generate 50% of the maximum response. |
| What is efficacy? | Effectiveness of a ligand or drug when eliciting a biological response |
| What is an agonist? | A compound (drug) that binds to a receptor and produces a biological effect that mimics the endogenous ligand. |
| What is an allosteric regulator? What is an example that acts on GABA receptors? | Enhances effects of an agonist; benzodiazepines bind to distinct site on GABA receptors and potentiate effects of GABA and GABA{A}-R by increasing frequency of Cl- channel opening without changing duration of channel opening (allosteric potentiation) |
| What is an antagonist? Do they have activity of their own? | A compound (drug) that binds to a receptor and blocks the action of its endogenous ligand or other agonists. Importantly, antagonists have no intrinsic activity of their own and produce no effect when binding to the receptor. |
| What is an comptetitive antagonist? How does it affect the maximum response? How does it affect potency? What type of shift is seen? Can it be surmounted by increasing concentration? | Binds to the same site as the agonist. Doesn’t change the maximum response of an agonist but decreases its potency (i.e. right shift of dose response curve; can be surmounted |
| Flumazenil is a specific competitive antagonist to what other type of drug? | Benzodiazepines |
| How should you adjust the concentration of competitive antagonist if amount of agonist in body increases? | Dose of competitive antagonist must be increased if the amount of agonist (endogenous or exogenous) in the body increases |
| What is a noncompetitive antagonist? | can either bind to the same site as the agonist but dissociate so slowly to essentially irreversibly block agonist binding or bind to a distinct site (allosteric antagonist) and block agonist binding. Potency unchanged, but max responce reduced |
| How should the dose of a noncompetitive antagonist change if there is an increase of agonist in the body? | Usually should not need to change (no increase necessary) |
| What is a partial agonist? | Compounds (drugs) that have efficacies greater than zero but less than that of a full agonist. Even if receptors are completely occupied by a partial agonist, a maximum biological response will not be generated (may act as antagonist) |
| How does aripiperazole work (receptor, agonist/antagonist) | Treats schizophrenia: partial agonist of D2 dopamine receptors (acts as antagonist while stimulating dopamine pathways when underactive) |
| What is an inverse agonist? | Bind and stabilize inactive conformation of a receptor. |
| Why would someone use inverse agonists vs. conventional antagonists? | Inverse agonists block the activity of constitutively active receptors, which would be relatively unaffected by conventional antagonists. |
| How does propananol work? | Inverse agonist that targets cells overexpressing Beta-2 adrenergic receptor: blocks downstream effectors that trigger cAMP production but activate other effectors coupled to this receptor that activate mitogen activated protein kinase (MAPK) |
Created by:
karkis77
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