7. Receptor Dynamics Flashcards
What is the main difference between pharmacodynamics and pharmacokinetics?
Pharmacodynamics refers to the effects of drugs on the body, while pharmacokinetics refers to the body’s effect on drugs.
What are receptors?
Proteins that selectively interact with hormones, neurotransmitters, or drugs to initiate biochemical events leading to a biological response.
How are receptors classified?
Receptors are classified based on structure, endogenous ligand, ligand binding properties, signal transduction, and amino acid sequences.
What processes regulate receptors?
Upregulation, downregulation, internalization, and desensitization.
What is receptor reserve?
The concept that not all receptors need to be occupied by a ligand to elicit a full biological response.
Fill in the blank: The relationship between ligand concentration and receptor occupancy can be expressed in _______.
[quantitative terms]
What information can be obtained from saturation binding curves?
The maximum binding capacity of a receptor and the affinity of the ligand for the receptor.
What are the characteristics of full agonists?
Activate receptors to produce a maximal biological response.
What distinguishes partial agonists from full agonists?
Partial agonists activate receptors but produce a less than maximal response.
How do competitive antagonists function?
They bind to the receptor but do not activate it, preventing endogenous agonists from binding.
How do noncompetitive antagonists differ from competitive antagonists?
Noncompetitive antagonists bind to the receptor at a different site than the agonist, reducing the overall response regardless of agonist concentration.
What is the significance of graded concentration response curves?
They illustrate the relationship between drug concentration and the magnitude of the response.
What is the role of G protein-coupled receptors (GPCRs)?
They use heterotrimeric GTP-binding proteins to regulate signal transduction.
True or False: Most drug-induced responses are mediated by receptors.
True.
What percentage of prescription drugs act at GPCRs?
30-40%.
What are the four major superfamilies of receptors?
- G protein-coupled receptors
- Ligand-gated ion channels
- Ligand-regulated transmembrane enzymes
- Cytosolic receptors
What is the physiological effect of cholera toxin?
It causes severe diarrhea due to increased cAMP production.
What is the clinical impact of pertussis toxin?
It prevents Gi from turning on, leading to increased cAMP production.
Fill in the blank: The primary function of a receptor is to mediate the effects of _______.
[endogenous ligands]
What are the major types of ligands?
- Endogenous ligands
- Synthetic ligands
What is the effect of Gs on adenylate cyclase?
It increases the activity of adenylate cyclase, leading to increased cAMP.
What happens when Gi is activated?
It decreases the activity of adenylate cyclase, leading to decreased cAMP.
What do ligand-gated ion channels do?
They open in response to ligand binding, allowing ions to flow across the membrane.
What is the role of cytosolic receptors?
They mediate responses to ligands that can cross the cell membrane.
What is the significance of receptor subtype classification?
It helps in developing drugs with tissue-specific actions.
What is a common example of a full agonist?
Beta agonists.
What are the effects of activation of phospholipase C (PLC)?
Increases IP3, diacylglycerol, and cytoplasmic Ca2+.
How does receptor internalization affect receptor signaling?
It reduces the number of available receptors on the cell surface, affecting the cell’s responsiveness to ligands.
Fill in the blank: The G protein cycle involves the exchange of GDP for _______.
[GTP]
What is the role of Protein Kinase A (PKA)?
It phosphorylates serine and threonine residues in target proteins.
What happens to the cAMP signal after it is produced?
It is terminated by phosphodiesterase, which converts cAMP to AMP.
What is the clinical significance of understanding receptor pharmacodynamics?
It aids in the development of targeted therapies and understanding drug actions.
What types of receptors can activate the same G protein?
β-ARs, D1 receptor, D5 receptor, V2 receptor, FSH receptor, LH receptor, H2 receptor, Glucagon receptor, ACTH receptor, 5-HT4 receptor, PGE2 receptor, Parathyroid hormone receptor
These receptors are examples of G protein-coupled receptors (GPCRs) that can converge on Gs proteins.
How many basic types of G proteins do hundreds of GPCRs converge on?
4 (Gs, Gi/o, Gq, G12/13)
This convergence allows for diverse physiological responses despite activation of the same G protein.
Why do receptors that activate Gs not induce identical physiological responses?
Different types of cells express different receptors and different downstream signaling proteins
This variability allows for specific responses to stimuli in different cell types.
What is the function of the thrombin receptor in G protein activation?
Inhibits adenylate cyclase and activates PLC
Thrombin receptor can activate G proteins Gi and Gq, leading to decreased cAMP and increased intracellular calcium.
What are the advantages of a signaling pathway with multiple steps?
Amplification of signal, specificity of response, integration of multiple signals
Multiple steps can enhance the sensitivity and versatility of cellular responses.
What is the typical structure of a GPCR?
7 transmembrane domains
These domains span the cell membrane and are involved in ligand binding and G protein activation.
What happens to β2-adrenergic receptors upon prolonged stimulation?
They switch to Gi coupling
This switch helps the cell adapt to prolonged exposure to stimulatory signals.
Fill in the blank: Ions cannot pass through the lipid bilayer of the cell membrane; their permeability is controlled by _______.
ion channels
Ion channels regulate the flow of ions across the membrane, affecting cellular functions.
What are the mechanisms of ion channel regulation?
Voltage-gated, ligand-gated, G protein interaction, second messenger binding
These mechanisms determine when and how ion channels open or close.
What is the effect of ligand-gated ion channels on membrane potential?
Change the membrane potential closer to or away from threshold
This action influences the excitability of the cell.
What is unique about nuclear receptors?
They are ligand-dependent transcription factors that bind specific DNA sequences
This allows them to regulate gene expression in response to hormonal signals.
What is the role of receptor tyrosine kinases in signal transduction?
Receptor dimerization and cross-phosphorylation to activate signaling cascades
This process is crucial for many growth factor signaling pathways.
Fill in the blank: Cytokine receptors activate the ______ pathway.
Jak-STAT
This pathway is important for mediating responses to cytokines in immune regulation.
What is the function of small G proteins like Ras?
They act as molecular switches in signaling pathways
Ras is involved in cell growth, differentiation, and survival signaling.
What is the significance of c-Src in cell signaling?
c-Src is a nonreceptor tyrosine kinase that phosphorylates transcription factors
This regulation is important for gene expression and cell growth.
True or False: v-Src is always inactive due to regulatory mechanisms.
False
v-Src is a viral oncogene that causes uncontrolled cell growth because it lacks the regulatory Tyr 527.
What do ligand-gated ion channels typically change in response to neurotransmitter binding?
Membrane potential and intracellular ion concentrations
This change can lead to excitatory or inhibitory effects in the target cell.
What is guanine?
A nucleotide
What does GAP stand for?
GTPase activating protein
Which protein is not a receptor-kinase?
Ras
What is the role of Shc and Grb2?
Adapter proteins
What is the function of scaffold proteins in kinase cascades?
Enables activation of specific signaling pathways
What happens if a cell loses control of the Ras signaling pathway?
Deregulation causes uncontrolled growth
What percentage of human cancers have mutant Ras proteins?
30%
What is the role of small G proteins like Ras?
Regulate diverse signaling pathways for cell growth, differentiation, and apoptosis
What is receptor desensitization?
Diminished response due to continued stimulation with an agonist
What is the purpose of receptor desensitization?
Prevents excessive stimulation by an agonist
What occurs during receptor internalization?
Receptor is targeted to clathrin-coated pit and internalized into endosome
What is receptor upregulation?
Increase in the expression of a receptor
What is receptor downregulation?
Decrease in receptor expression
What effect does thyroid hormone have on cardiac β-adrenergic receptors?
Regulates their expression
What is the association rate constant (K1)?
Rate at which ligand and receptor form a complex
What is the equilibrium dissociation constant (Kd)?
Ligand concentration at which 50% of receptors are occupied
What does a high Kd indicate?
Low affinity
What does a low Kd indicate?
High affinity
What is intrinsic activity in the context of receptor-ligand interactions?
Ability of a ligand to activate a receptor upon binding
What characterizes a full agonist?
Affinity for RA much greater than RI
What characterizes a partial agonist?
Affinity for RA greater than RI, activates receptor with submaximum efficacy
What is the intrinsic activity of an antagonist?
0
What is the function of nuclear receptors?
Signal transduction to the nucleus
Fill in the blank: Phosphorylated receptor tyrosine kinases serve as _______ for proteins involved in downstream signaling.
docking sites
What is the role of β-arrestin in receptor desensitization?
Prohibits interaction with G protein and targets receptor for internalization
What is the consequence of prolonged use of β-adrenergic antagonists?
Tolerance develops
What is the effect of ligand characteristics on receptor activation?
Affinity and intrinsic activity determine receptor activation
What is the significance of receptor subtype existence?
Enables development of drugs with tissue-selective effects
What happens when ligand concentration equals Kd?
50% of receptors are bound to ligand
What is the formula for fractional receptor occupancy?
[L] / ([L] + Kd)
What indicates receptor activation in the context of GPCR?
Interaction with G protein
What is a characteristic of inverse agonists?
Affinity for RA much lower than RI
What is a key mechanism of action for nonreceptor tyrosine kinases?
Signal transduction pathways
What is the time frame for ligand-gated ion channels to respond?
Milliseconds
What is the time frame for cytosolic receptors to respond?
Hours
What is an agonist?
A substance that activates a receptor with intrinsic activity > 0.
What defines a partial agonist?
Activates receptor with intrinsic activity between 0 and 1, producing a submaximal response.
What is the intrinsic activity of an antagonist?
Intrinsic activity = 0; does not activate the receptor.
What is an inverse agonist?
A substance that decreases the response below the basal level with intrinsic activity < 0.
What is EC50?
Concentration of a drug required to produce 50% of that drug’s maximal effect; a measure of potency.
Define efficacy in pharmacology.
Magnitude of drug-induced response.
What is the difference between graded and quantal concentration-response curves?
Graded curves show continuous response; quantal curves show all-or-nothing responses.
What does ED50 represent?
Median effective dose; dose at which 50% of individuals exhibit a specified quantal effect.
What is TD50?
Median toxic dose; dose that causes a specified toxic effect in 50% of experimental animals.
Define LD50.
Median lethal dose; dose that causes death in 50% of experimental animals.
What formula defines the therapeutic index?
Therapeutic index = TD50 / ED50.
How does receptor reserve affect agonist potency?
A drug will be more potent in tissues with receptor reserve than in those without.
What is the role of receptor density in drug response?
Higher receptor density can enhance the effect of an agonist.
Fill in the blank: A partial agonist will not produce a maximal response even when _____ of the receptors are occupied.
100%
What is the effect of a full agonist in the presence of a partial agonist?
The partial agonist acts as an antagonist.
What is competitive antagonism?
Binds reversibly to the receptor and can be overcome by high agonist concentration.
What happens to the concentration-response curve with a competitive antagonist?
Causes a rightward shift; no effect on maximal response.
What defines a noncompetitive antagonist?
Binds irreversibly or modifies the receptor, decreasing maximal response.
How does the duration of action of a noncompetitive antagonist depend on?
Rate of new receptor synthesis rather than drug elimination.
What is chemical antagonism?
One drug inhibits the actions of a second drug by binding to it.
What is physiological antagonism?
Two drugs work through separate receptors and pathways to produce opposite effects.
What effect does receptor reserve have on a drug’s potency?
A drug will be more potent in tissues with a receptor reserve.
True or False: A quantal dose-response curve can be made for any type of drug.
True.
