Desensitization, Phospholipase C and Calcium Flashcards
What is desensitization?
Reduced responsiveness of a tissue to an agonist that develops in response to the continuous or repeated stimulation
How is GPCR desensitization induced?
Receptor phosphorylation by PKA and B-arrestin binding to the receptor
How does PKA repress the B-adrenergic receptor?
When B-adregernic receptor binds epinephrine, PKA phosphorylates the cytosolic domain that normally interacts with Gs protein, diminishing its capacity to activate Gs.
The intensity of the signal by further stimulation will be diminished while its phosphorylated.
Affinity for epinephrine is not changed
Why does any signaling molecule that activated PKA have the ability to desensitize other GPCRs?
Because PKA will have its inhibitory affect regardless of what initial molecule activates the pathway.
What are G protein coupled receptor kinases (GRKs)?
Kinases that phosphorylate specific serine and threonine residues on the cytosolic domain of GPCRs only when the receptor isn in an active conformation by ligand or agonist binding
What is B-adrenergic receptor kinase (B-ARK)?
a GRK that phosphorylates specific serine and threonine residues on the B-adrenergic receptor.
These phosphorylated residues serve as binding sites for B-arrestin
What is B-arrestin?
A scaffolding protein that recruits other cytoplasmic proteins.
Binds to phosphorylated B-adrenergic receptor and blocks coupling to G proteins
After B-arrestin binds B-adrenergic receptor, what proteins does it recruit?
Clathrin and AP2 which promote endocytosis of the receptor.
Can also bind proteins that link the GPCR to other signal transduction pathways
E.g. Map kinase cascade/Jun kinase cascade
What are two fates of the internalized B-adrenergic receptors that are endocytized?
They can be degraded, resulting in a net decrease in receptor content
The can be dephosphorylated and translocated back to the plasma membrane
What are Gq proteins?
A family of heterotrimeric G proteins that activate the B isoform of phospholipase C
What is the function of Phospholipase C-B?
Catalyzes the hydrolisis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG)
PIP2 –> IP2 + DAG
What is the function of diacylglycerol (DAG)?
A lipophilic molecule that remains in the plasma membrane where it binds to and activates certain isoforms of protein kinase C
What is the function of inositol 1,4,5-triphosphate (IP3)?
Diffuses into the cytosol and binds to the receptor domian of IP3-gated Ca2+ release channels on the ER
What happens as a result of the increase in Ca2+ from IP3 activation of ER calcium channels?
- Recruitment of PKC to the plasma membrane
- binding of Ca2+ to calmodulin
What are the three isoforms of PKC and what is required for each activaiton?
Conventional - DAG, Ca2+, phosphatidylserine
Novel - DAG phosphatidylserine
Atypical - no regulatory domain