PD Principles: Effect of Drugs on Receptors & Cell Signaling; Receptor Features and Interactions Flashcards
The majority of drugs produce their effect by interacting with biomolecules at _____, which are divided into _____ and _____.
sites of action; receptors, non-receptors
What are the receptors for sites of action?
Ligand-Gated Ion channels G-protein Coupled Receptors (GPCR) Receptor Tyrosine Kinase (RTK) Cytokine Receptors Nuclear Receptors (Types I & II)
What are the non-receptors for sites of action?
Enzymes (ex. CYP 450 (CYP 3A4, 2D6, etc)
Ion channels
Transporters (ex. p-glycoprotein (p-gp), OCT, OAT)
Define Receptors.
A component that is “receptive” to interacting with drugs or endogenous substances and is capable of initiating a subsequent response
Define Receptor Site (i.e. Binding Site).
The specific region of the receptor molecule at which the drug binds.
What are the two main functions of receptors?
o Sensing ligand
• Ligand is 1st messenger
• Ligand binding domain on the receptor
o Signal transduction
• Signal propagation; effector domain → elicits a response
• Example: α-subunit activation of adenyl cyclase→ ↑[cAMP] → activates PKA → phosphorylates Ser/Thr on peptides
What kinds of responses are elicited by signal transduction?
Ligand binding Possible receptor events Second messengers Downstream response Effect
What is Ligand Binding?
o Ligand is 1st messenger
o Receptor conformation is important
o Different receptor types or sub-types may bind same ligand
What are possible receptor events?
o Conformational changes
o Dimerization
o Activation event
o Inactivator release
What are secondary messengers?
o Catalytic enzymes (Adenylyl cyclase, PDE)
o Signaling molecules
• α, β, γ -subunits of GPCR
• JAK/STAT accessory proteins
What are downstream responses?
o Enzyme activation o Activation of ligand channel o Transcription regulation o Receptor regulation (Down-regulation, sequestration) o Cross talk
What are the effects of signal transduction?
o Gene transcription, cell proliferation, migration, apoptosis, survival
o Vasodilation, vasoconstriction, etc.
What are the Important Features of Receptors?
Structural Specificity:
o Ligand or drug binding
o Stereospecificity
Saturability:
o Receptors exist in finite numbers
o can be saturated by high concentrations (i.e. doses) of drug.
o Therefore, increasing the dose after saturating (occupying) all receptors will NOT increase its response any further
Response:
o Pharmacological response and its magnitude depends on
• The amount of drug reaching its site of action (pharmacokinetic consideration)
• The drug‐receptor interaction at that site
o # of receptors occupied, chemical forces (i.e. covalent bond, hydrogen bond)
• The functional status of the receptor and/or target cell
Regulation:
o Receptors are dynamic entities that can be affected by physiological, pharmacological
and pathological factors
• Tolerance, desensitization, down-regulation, up-regulation, etc
What is the lock and key drug receptor interaction?
• The drug (the key) combines with a receptor (the lock) to produce a pharmacological effect.
o Drugs that will fit into the receptor are said to have an “affinity” for that receptor-site.
• **Most Drug-Receptor Interactions (i.e. binding) are REVERSIBLE
o Most Drug Binding Interactions do NOT form Covalent Bonds
_____ signals transmitted to _____ and _____.
Extracellular; cytoplasm, nucleus
Modify post-receptor signaling via second messengers
– Generate, amplify, coordinate, and terminate signaling
