Lecture 2: How Drugs Bind to their Targets Flashcards
What are modes of signal transmission?
Common mechanisms by which receptors interact with drugs and generate a signal in the cell which causes a biological response
How can a drug get to intracellular recptors?
Because the receptor is on the inside of the cell, the drug has to cross the membrane in order to get to the receptor
What properties must the drugs that target intracellular receptors have?
They must be lipid soluble (hydrophobic) or have some other transport mechanism in order to cross the cell
What are examples of drugs that can bind to intracellular receptors?
Steroid hormones: Glucocorticoids, anabolic steroids etc
What is the Mode of Action of substances that bind to Intracellular Receptors?
They bind to the Ligand binding Domain (LBD) of a steroid hormone receptor, leading to the displacement of the Heat Shock Protein (HSP) or other chaperone. This exposes a DNA recognition domain and leads to the activation of transcription target genes
What is the relative timing of intracellular receptors?
Its effects typically have slow onset and are long lasting (not rapidly reversible)
Why is the relative timing of Intracellular receptors slow?
Because it requires transcription and gene synthesis
What kind of receptors are G-protein coupled receptors (GPCRs)?
Transmembrane receptors
Which side do ligands bind to on G-protein coupled receptors?
They bind to the extracellular side
What generally happens once ligands bind to the extracellular side of GPCRs?
The ligand triggers a conformational change that activates a signaling cascade mediated by intracellular G-proteins
What are the G-proteins distinct from?
The receptor
What does the activation of the receptor do in G proteins?
Promotes the exchange of GDP for GTP
What is meant by the G-alpha subunit has GTPase activity?
It acts like a molecular timer or countdown to terminate the signal and hydrolyzed GTP to inactivate the G-protein complex
What can active G-proteins do?
Influence effector proteins that alter cellular activity
What are the three intracellular G-proteins that a receptor is coupled with?
- G-alpha
- G-beta
- G-gamma
What is G-alpha bound to at rest?
GDP
What happens once G-alpha binds to GTP?
It dissociates from the G-protein complex and acts as an effector
When a receptor is activated what do the G-beta and G-gamma subunits usually stay associated with?
The membrane
What can the G-beta and gamma subunits do?
They can directly activate various downstream effectors like ions channels or recruitment of kinases
What are the three types of G-alpha subunits?
- Gs
- Gi
- Gq
What can the different types of G-alpha do?
Influence different signalling cascades
What are the two main targets of the alpha subunit of G proteins?
Adenylate cyclase (AC) and phospholipase C (PLC)
What does the Gs type of alpha subunit do?
Activates Adenylate Cyclase
What does the Gi type of Alpha subunit do?
Inhibits Adenylate Cyclase
