Signaling #8 Flashcards
What is the role of PIP2 breakdown in GPCR signaling?
It is linked to the activation of Tubby transcription factor and increased opening of TRPV1 ion channel under inflammatory conditions.
TRPV1 is sensitive to heat, protons, and capsaicin.
What type of signaling is involved in the activation of phosphorylase kinase?
cAMP and Ca++ mediated signaling.
How does GPCR signaling stop?
Through modification, degradation, or downregulation of receptors, and short lifespan of second messengers.
What is desensitization in GPCR signaling?
A process where receptors become less responsive to stimulation after activation.
What is the role of PKA and PKC in GPCR desensitization?
They phosphorylate serine and threonine residues at consensus sequences in the GPCR, leading to desensitization.
What are GRKs and their function in GPCR signaling?
G protein-coupled receptor kinases that phosphorylate ligand-bound GPCRs, facilitating desensitization.
What happens during homologous desensitization?
Only activated receptors undergo desensitization via GRKs and arrestins.
What is the difference between receptor desensitization and down-regulation?
Desensitization is rapid and reversible; down-regulation involves removal from the cell surface and is slower.
What initiates receptor down-regulation?
The internalization of activated receptors into clathrin-coated pits.
What is the role of arrestins in GPCR desensitization?
They sterically uncouple G-proteins from receptors and serve as scaffolding proteins for internalization machinery.
What occurs after the binding of arrestins to phosphorylated GPCRs?
Arrestins facilitate internalization of the receptor and prevent further G-protein activation.
What is the function of E3 ubiquitin ligase in GPCR down-regulation?
It ubiquitinates dephosphorylated arrestin, facilitating the endocytosis of the receptor.
True or False: GRKs are only located in the cytoplasm.
False.
Fill in the blank: The active Gα-GTP complex is able to stimulate a number of _______.
[signaling pathways]
What happens to the receptor after it is internalized?
It can be recycled back to the plasma membrane or directed to lysosomal degradation.
What is the significance of phosphorylation sites on GRK2?
They influence GRK2’s activity and its ability to bind Gβγ subunits.
How does persistent agonist stimulation affect GPCRs?
It leads to receptor down-regulation through internalization.
What is the role of dynamin in GPCR internalization?
It pinches off clathrin-coated pits to internalize the receptor complex.
What does PKA phosphorylation of β2AR alter?
It alters the receptor coupling from Gs to Gi
Activated Gi subsequently deactivates Gs protein, resulting in a decrease in cAMP production and PKA activity.
What is the role of phosphorylation of the C-terminal region of GPCRs by PKA or PKC?
It decreases affinity for interaction of this region with the G-protein
PKA (Gs) and PKC (Gq; DAG) are involved in this phosphorylation.
True or False: GRK2 is involved in the desensitization of GPCR signaling.
True
Dysregulation of this desensitization can lead to pathological challenges.
What is angioedema?
Swelling under the skin, similar to hives, usually due to a trigger like a medicine or allergy.
What does the Cre-Lox system allow researchers to generate?
Tissue-specific and inducible knockouts
This provides control over the location and timing of gene expression.
What is the function of the Tie2-Cre transgene?
It directs expression of Cre recombinase to endothelial cells
Useful for deletion of floxed sequences like GRK2.
What was assessed in Tie2CRE-GRK2fl/− mice in the study?
Extravasation and vascular permeability in response to BK
Evans Blue dye leakage was measured.
What is the effect of inhibiting GRK?
It allows BK signaling to continue, making membranes leaky.
What was the correlation found between GRK2 levels and angioedema severity?
A significant inverse correlation
Higher GRK2 levels were associated with lower severity scores.
What happens to GRK2 levels in bovine aortic endothelial cells after BK stimulation?
GRK2 increases at 5 min and returns to baseline at 15 min.
Fill in the blank: GRK2 is a type of _______.
G protein-coupled receptor kinase.
What is the role of GRK2 in the pathophysiology of vascular permeability?
It is a pivotal regulator of BK signaling.
What effect does PKA have on β2ARs in terms of G-protein interaction?
It switches from a Gs to a Gi interacting GPCR.
What is the significance of GRK2 levels in patients with C1-INH hereditary angioedema?
Reduced GRK2 levels correlate with a severe phenotype of angioedema.
What does GRK2 phosphorylation of GPCRs result in?
Desensitization of the receptor.
What is the effect of PKA and PKC on GPCRs?
They phosphorylate distinct regions on the C-terminal region.
