L2. GPCR signalling in the heart

Question 1

What is the most common system of cell surface receptors in humans?

Answer 1

G-protein coupled receptors (GPCRs)

Question 2

How many GPCRs are expressed in humans?

Answer 2

Approximately 800

Question 3

What percentage of drugs target GPCRs?

Answer 3

Nearly half of all known drugs

Question 4

What happens when a ligand binds to a GPCR?

Answer 4

It activates the associated G-protein, causing a conformational change

Question 5

What are the subunits of a G-protein?

Answer 5

Alpha, beta, and gamma subunits

Question 6

What is the function of Gαs in GPCR signaling?

Answer 6

It activates adenylate cyclase to produce cyclic AMP

Question 7

How does Gαi differ from Gαs?

Answer 7

Gαi inhibits adenylate cyclase, reducing cyclic AMP levels

Question 8

What pathway does Gαq activate?

Answer 8

The phospholipase C pathway, leading to calcium release

Question 9

Why are GPCR structures important for drug development?

Answer 9

They provide insights for designing specific ligands

Question 10

What is the significance of X-ray crystallography in GPCR studies?

Answer 10

It reveals the 3D structure of GPCRs at atomic resolution

Question 11

What is cryo-electron microscopy’s advantage over X-ray crystallography?

Answer 11

It studies GPCRs in solution, preserving their native conformation

Question 12

How do biased ligands affect GPCR signaling?

Answer 12

They selectively activate either G-protein or β-arrestin pathways

Question 13

What is β-arrestin’s role in GPCR signaling?

Answer 13

It desensitizes GPCRs and mediates receptor internalization

Question 14

What is GPCR desensitization?

Answer 14

The process by which receptor activity decreases in response to sustained stimulation

Question 15

How do endosomes contribute to GPCR signaling?

Answer 15

Internalized GPCRs can signal from endosomal membranes

Question 16

What is the primary effect of β1 adrenergic receptors in the heart?

Answer 16

They increase heart rate and contractility

Question 17

How do β2 adrenergic receptors differ in signaling?

Answer 17

They can signal via both Gαs and Gαi pathways

Question 18

What role does angiotensin II play in GPCR signaling?

Answer 18

It activates Gαq, increasing calcium levels and promoting vasoconstriction

Question 19

What was the TRV027 compound developed for?

Answer 19

To selectively activate the β-arrestin pathway for cardioprotection

Question 20

Why did TRV027 fail in clinical trials despite promising animal data?

Answer 20

Differences in receptor isoforms and species-specific effects

Question 21

What is the function of inverse agonists in GPCR signaling?

Answer 21

They inhibit receptor activity by binding to the orthosteric site

Question 22

What is biased signaling in GPCRs?

Answer 22

Selective activation of specific downstream pathways by a ligand

Question 23

What are allosteric modulators?

Answer 23

Compounds that bind to sites distinct from the orthosteric site, modulating receptor activity

Question 24

What does the term ‘balanced ligand’ refer to?

Answer 24

A ligand that activates both G-protein and β-arrestin pathways equally

Question 25

What is the role of GPCRs in heart failure treatment?

Answer 25

They are targeted by drugs like beta-blockers to reduce cardiac workload

Question 26

How does chronic β1 adrenergic stimulation affect the heart?

Answer 26

It can lead to apoptosis and adverse remodeling

Question 27

What is the cardioprotective effect of β2 adrenergic receptor signaling?

Answer 27

It signals via Gαi, reducing apoptosis

Question 28

What is structural-based drug development?

Answer 28

Using GPCR structures to design ligands with high specificity

Question 29

What is the significance of GPCR signaling from endosomes?

Answer 29

It adds complexity by enabling sustained signaling

Question 30

How do GPCRs signal from internal membranes like mitochondria?

Answer 30

Through constitutively expressed receptors on these membranes

Question 31

What technique was used to demonstrate GPCR endosomal signaling?

Answer 31

Fusion of GFP to GPCRs to track receptor internalization

Question 32

What was shown by parathyroid hormone receptor studies?

Answer 32

Sustained cyclic AMP signaling from internalized receptors

Question 33

Why is endosomal signaling a challenge for drug design?

Answer 33

Drugs must be membrane-permeable to affect internalized receptors

Question 34

How do biased agonists benefit therapeutic design?

Answer 34

They target specific pathways, minimizing off-target effects

Question 35

What is an example of a GPCR-targeted drug?

Answer 35

Metoprolol, a beta-blocker used in heart failure

Question 36

What is the relevance of GPCR complexity to drug development?

Answer 36

It requires consideration of cross-talk and pathway specificity

Question 37

What is the therapeutic goal of β-arrestin biased ligands?

Answer 37

To provide cardioprotection while minimizing adverse effects

Question 38

How does ligand-induced GPCR conformation affect signaling?

Answer 38

Different ligands stabilize unique receptor conformations

Question 39

What is the role of water displacement in ligand binding?

Answer 39

It stabilizes ligand-receptor interactions energetically

Question 40

What is a major challenge in translating animal GPCR research to humans?

Answer 40

Species-specific receptor isoform differences