Signaling #9

Question 1

What should you know about GPCR signaling by the end of the lecture?

Answer 1

Different ways in which GPCR signaling stops and the process of GPCR desensitization and internalization

Includes the role of β-arrestin as an adaptor molecule in GPCR desensitization.

Question 2

What is angioedema?

Answer 2

Swelling similar to hives, but occurring under the skin instead of on the surface

Hereditary Angioedema (C1-INH-HAE) is a rare condition affecting ~6,000 people in the US.

Question 3

What is the role of GRK2 in angioedema?

Answer 3

Decreased GRK2 levels are associated with pathologies like angioedema

GRK2 plays a pivotal role in the regulation of vascular permeability.

Question 4

What is the midterm exam format?

Answer 4

Multiple choice (~20) and 2 short answer questions, lasting 50 minutes

Scheduled for Monday, February 10th, from 10:30 to 11:20.

Question 5

What initiates GPCR desensitization?

Answer 5

Activation of the receptor by ligand binding

This process requires the receptor to be activated.

Question 6

Name two key players in GPCR desensitization.

Answer 6

• 2nd messenger dependent protein kinases (e.g., PKA, PKC)
• G protein coupled R kinases (GRKs)

These components phosphorylate the ligand-bound GPCR.

Question 7

What is the effect of PKA and PKC phosphorylation on GPCR?

Answer 7

Prevents efficient interaction of G-proteins with the ligand-bound receptor

This leads to desensitization of the receptor.

Question 8

How do GRKs contribute to GPCR desensitization?

Answer 8

Phosphorylate ligand/agonist bound GPCRs at serine and threonine residues

They can be recruited to the cell membrane via interactions with activated βγ subunits.

Question 9

What do arrestins do in GPCR desensitization?

Answer 9

Sterically uncouple trimeric G-protein from receptor and serve as scaffolding proteins

They increase the affinity for β-arrestin, facilitating internalization.

Question 10

What is homologous desensitization?

Answer 10

A two-phase process involving receptor desensitization and down-regulation

Phase 1 occurs soon after agonist stimulation, while Phase 2 involves internalization.

Question 11

What happens when GPCR signaling desensitization is dysregulated?

Answer 11

It can lead to pathological challenges such as angioedema

Dysregulation affects vascular permeability.

Question 12

What animal model is used to study endothelial-specific GRK2 knockouts?

Answer 12

Tie2-CRE/GRK2 fl+/fl- mice

These mice exhibit altered GRK2 levels in endothelial cells.

Question 13

What was the conclusion regarding GRK2 levels in angioedema patients?

Answer 13

Reduced GRK2 levels correlate with severe phenotype of angioedema

This establishes GRK2 as a regulator of BK signaling.

Question 14

What happens to mice lacking β-arrestin?

Answer 14

Cardiac β1-AR becomes supersensitive, enhancing heart muscle contractile response

This indicates the role of β-arrestin in normal GPCR function.

Question 15

What occurs during resensitization of GPCRs?

Answer 15

Recycling of receptors back to the membrane

This process is not common and is a form of GPCR regulation.

Question 16

What is cell supersensitization in the context of GPCRs?

Answer 16

Cell increases GPCR expression when ligand levels are low

This occurs as a compensatory mechanism.

Question 17

What is the effect of β-blockers on GPCR signaling?

Answer 17

They make the body think there is very little actual ligand around

This can lead to increased sensitivity upon withdrawal.

Question 18

What is the role of β-blockers in relation to β-adrenergic receptors?

Answer 18

β-blockers block the ability of ligands to bind to β-adrenergic receptors (βARs)

This leads to an increase in the production of more receptors due to perceived low levels of ligand.

Question 19

What is the recommended method for discontinuing β-blockers?

Answer 19

Gradual withdrawal is better than sudden withdrawal (cold turkey)

Sudden withdrawal can lead to increased sympathetic stimulation of the heart, increased heart rate, and angina pectoris.

Question 20

What happens to βARs when a person discontinues β-blockers?

Answer 20

There are too many receptors for endogenous ligand to bind to

This occurs due to the body producing more receptors in response to the blocked binding of adrenaline.

Question 21

What is desensitization in the context of GPCRs?

Answer 21

Desensitization may be an adaptive response to activating the GPCR, but can lead to pathological loss of receptor signaling.

Question 22

What is the significance of GRK2 expression in heart failure?

Answer 22

GRK2 expression and activity are increased in human heart failure

It has been implicated in βAR desensitization and compromised cardiac function.

Question 23

What is a novel early marker for cardiac dysfunction?

Answer 23

Elevation of GRK2 often precedes the development of clinical heart failure.

Question 24

What does GRK2/βARK1 stand for?

Answer 24

Beta adrenergic receptor kinase 1.

Question 25

How does compromised βAR signaling affect cardiac function?

Answer 25

Impaired βAR signaling compromises cardiac sensitivity to inotropic stimulation.

Question 26

What mechanism leads to βAR uncoupling during CABG?

Answer 26

Increased GRK2 activity is the primary mechanism of βAR uncoupling during coronary artery bypass grafting (CABG).

Question 27

What is the relationship between GRK2 activity and hypertension?

Answer 27

Transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed elevated resting blood pressure.

Question 28

What is a potential therapeutic target to prevent compromised heart function?

Answer 28

GRK2 inhibitor peptide may serve as a therapeutic target ## Footnote It binds but has no catalytic activity, thus not phosphorylating GPCRs.

Question 29

What is the effect of the C-terminal domain of GRK2 when transgenically expressed?

Answer 29

It improves cardiac performance by inhibiting GRK2's ability to phosphorylate ligand-bound βARs.

Question 30

What is Oguchi disease?

Answer 30

A rare autosomal recessive form of congenital stationary night blindness ## Footnote It is linked to mutations in arrestin and GRK1.

Question 31

What is the function of GRK1 (Rhodopsin kinase) in humans?

Answer 31

It is a rod-specific cytosolic enzyme that phosphorylates multiple serine residues on photoactivated rhodopsin GPCR.

Question 32

True or False: Increased GRK2 activity is beneficial for heart function.

Answer 32

False ## Footnote Too much GRK2 activity contributes to a hypertensive state.

Question 33

Fill in the blank: Proper regulation of _______ is important for heart function.

Answer 33

βAR signaling.