Receptor theory I Flashcards
What 4 target proteins can drugs bind to?
- Receptors
- Enzymes
- Transporters/carriers
- Ion channels
What are receptors?
- Translate extracellular message –> intracellular change
- Recognise and respond to endogenous chemicals
How are receptors identified and classified?
Structure, pharmacology and signalling
What are examples of endogenous compounds which receptors respond to?
Neurotranmitters and neuropeptides
What can happen if increase the concentration of a drug high enough, with a receptor that is doesn’t normally bind to?
What does this show?
Eventually will bind to the receptor - shows that no receptor is 100% specified
And that no drug acts with TOTAL specificity
How many transmembrane domains do G-protein receptors have?
7
How many transmembrane domains do ligand-gated receptors have?
4
How many transmembrane domains do kinase-linked receptors have?
1
How many transmembrane domains do nuclear receptors have?
0
What is another name for GPCR?
Metabotropic
What is another name for ligand-gated channels?
Ionotropic
Where are the N’ and C’ terminus of a GPCR?
N extracellular
C intracellular
Where are the N’ and C’ terminus of a ligand-gated channel?
Both extracellular
Where are the N’ and C’ terminus of a kinase-linked receptor?
N is intracellular
C is extracellular
What is the structure of a GPCR?
- 3 intracellular loops
- 7 transmembrane domains
- N’ extracellular
- C’ intracellular
How does the signalling of a GPCR occur? (heterotrimeric)
Through a cascade:
1) Ligand bind, activate GPCR
2) Creates Gprotein docking region
3) G protein bind
4) GDP released from Gprotein
5) GTP bind to Gprotein
6) alpha subunit dissociates from BY subunits
7) Activates other proteins/receptors
What are the different alpha subunits of a Gprotein and what do they cause to happen?
1) Gs
- Stimulates adenylyl cyclase and guanylyl cyclase
2) Gi
- Inhibits AC ad GC
3) Gq
- Stimulates phospholipase C
What are the 2 different types of Gprotein and how are they different?
1) Monomeric - made of one protein
2) Heterotrimeric - made of 3 DIFFERENT proteins (alpha, beta, gamma)
How is the signalling of a heterotrimeric Gprotein stopped?
1) a subunit self hydrolyses GTP –> GDP
2) a subunit becomes inactivated
3) a subunit has high affinity for the BY subunit
What do the BY subunit of the Gprotein activate?
Ligand-gated ion channels
Which Gprotien subunits are bound to the plasma membrane?
alpha and gamma
What does arrestin do?
Binds the the GPCR and stops the signalling
What does phospholipase C do when is activated?
1) Hydrolyses PIP2 (membrane bound) into DAG (membrane bound) and IP3 (Cytosolic messenger)
2) IP3 diffuses into the ER
3) Releases Ca2+ stored in the ER into the cytosol
4) Ca2+ bind to receptors and cause further signalling events
5) Ca2+ causes PKC to move to the plasma membRane
6) PKC activated by DAG and bound CA2+
What does activated protein kinases do?
Phosphorylates target proteins on serine and threonine residues
What is PKA activated by?
ATP
What is PKC activated by?
Calcium
What are the 2 different types of kinase-linked receptors?
1) Receptors can BE a tyrosine kinase
2) Receptors can be ASSOCIATED with a tyrosine kinase
What is an example of a monomeric Gprotein?
Ras GTPase
What are Ras GTPases activated by?
- Activating Ras-GEF
- Inhibiting Ras-GAP
What is Ras-GEF and what do they do?
- Guanine nucleotide exchange factors
- Promote exchange of bound GDP –> GTP
- Activate Ras
What is Ras-GAP and what do they do?
- GTPase - activating proteins
- Increase speed of GTP synthesis
Inactivate Ras
What are Ras GTPases activated by
GDP–> GTP
What are the downstream targets of receptor tyrosine kinases?
1) Map kinases, through a monomeric Gprotein (Ras GTPase)
2) PI3 kinases
3) Phospholipase C (gamma)
What are the stages which occur when a receptor tyrosine kinase is activated?
1) Autophosphorylation or crossphorylation at the kinase domain
2) Then, can phosphorylate each other at tyrosine residues
3) Provides binding/docking/activation sites for other signalling molecules
Examples of GPCR?
- Muscarinic acetylcholine receptors
- Rhodopsin
- Opiate receptors
- Dopamine receptors
- Canaboid receptors
Examples of kinase-linked receptors?
- Cytokines
- Chemokines
- Growth factors
