GPCRs 1 Flashcards
What are the three types of GPCRs?
Gs coupled, Gi/Go coupled and Gq coupled.
What are Gs coupled receptors?
Stimulatory receptors. An agonist binding causes a conformation change that allows the G protein to affect downstream signals. Adenyl cyclase is activated that causes ATP to activate cAMP to cause PKA to be activated.
What are Gq coupled receptors?
Receptors that activate phospholipase C to cause calcium release through activation of IP3 from PIP2. In this process DAG also activates PKC.
What are Gi/Go coupled receptors?
They inhibit adenylyl cyclase, cause potassium channels to open and inhibit calcium channels.
What is the basic mechanism behind GPCRs?
An agonist binds to the receptor to cause GTP to be converted into GDP as an energy source to cause downstream intracellular reactions.
What is the basic structure of a GPCR?
The G protein is tethered to the membrane and there is an extracellular N terminus, 7 transmembrane alpha helices, three extracellular looks and an intracellular C terminus.
What is desensitization?
The agonist-induced loss of function.
What curve does a desensitization curve have similarities to?
Irreversible antagonist.
How can GPCR desensitization be studied?
Any functional responses that involve GPCR activation: functional assays (e.g. guinea pig ileum), cell-based assays (inhibition of calcium release measuring cAMP levels), electrophysiology (opening of potassium channels), GTPgamma35s - radioligand binding - measures the binding of a ligand to the extravellular part. It is a measure of receptor activation.
What is the mechanism behind G-protein receptor desensitization?
GRK (G-protein-coupled receptor kinase) phosphorylates serine residues on the active GPCRs which allow another protein to bind to the receptor. Arrestin has a low affinity for the unphosphorylated receptor and a high affinity for the phosphorylated receptor. Arrestin is now a high affinity ligand for this part of the receptor and blocks the path for the G protein to bind with the receptor to desensitize it.
What is the importance of receptor desensitization?
Homeostasis - it protects cells from being excessively activated e.g. in the heart a spike of adrenaline needs to be controlled in order to reduce these levels.
What is a problem with receptor desensitization in terms of medication?
There will be tolerance problems to the drug due to desensitization. An increasing dose will be required to have the same effect.
How can desensitization/drug tolerance be reduced?
Inhibiting the desensitization (such as GRK inhibitor), allosteric modulators, functional selectivity, agents to affect receptor internalization, inverse agonists.
What are allosteric modulators?
They do not activate a receptor themselves but modulate the response that occurs when an agonist binds.
What is an example of an allosteric modulator?
Benzodiazepines at GABA receptors.
