L2. GPCR signalling in the heart Flashcards
What is the most common system of cell surface receptors in humans?
G-protein coupled receptors (GPCRs)
How many GPCRs are expressed in humans?
Approximately 800
What percentage of drugs target GPCRs?
Nearly half of all known drugs
What happens when a ligand binds to a GPCR?
It activates the associated G-protein, causing a conformational change
What are the subunits of a G-protein?
Alpha, beta, and gamma subunits
What is the function of Gαs in GPCR signaling?
It activates adenylate cyclase to produce cyclic AMP
How does Gαi differ from Gαs?
Gαi inhibits adenylate cyclase, reducing cyclic AMP levels
What pathway does Gαq activate?
The phospholipase C pathway, leading to calcium release
Why are GPCR structures important for drug development?
They provide insights for designing specific ligands
What is the significance of X-ray crystallography in GPCR studies?
It reveals the 3D structure of GPCRs at atomic resolution
What is cryo-electron microscopy’s advantage over X-ray crystallography?
It studies GPCRs in solution, preserving their native conformation
How do biased ligands affect GPCR signaling?
They selectively activate either G-protein or β-arrestin pathways
What is β-arrestin’s role in GPCR signaling?
It desensitizes GPCRs and mediates receptor internalization
What is GPCR desensitization?
The process by which receptor activity decreases in response to sustained stimulation
How do endosomes contribute to GPCR signaling?
Internalized GPCRs can signal from endosomal membranes
What is the primary effect of β1 adrenergic receptors in the heart?
They increase heart rate and contractility
How do β2 adrenergic receptors differ in signaling?
They can signal via both Gαs and Gαi pathways
What role does angiotensin II play in GPCR signaling?
It activates Gαq, increasing calcium levels and promoting vasoconstriction
What was the TRV027 compound developed for?
To selectively activate the β-arrestin pathway for cardioprotection
Why did TRV027 fail in clinical trials despite promising animal data?
Differences in receptor isoforms and species-specific effects
What is the function of inverse agonists in GPCR signaling?
They inhibit receptor activity by binding to the orthosteric site
What is biased signaling in GPCRs?
Selective activation of specific downstream pathways by a ligand
What are allosteric modulators?
Compounds that bind to sites distinct from the orthosteric site, modulating receptor activity
What does the term ‘balanced ligand’ refer to?
A ligand that activates both G-protein and β-arrestin pathways equally
What is the role of GPCRs in heart failure treatment?
They are targeted by drugs like beta-blockers to reduce cardiac workload
How does chronic β1 adrenergic stimulation affect the heart?
It can lead to apoptosis and adverse remodeling
What is the cardioprotective effect of β2 adrenergic receptor signaling?
It signals via Gαi, reducing apoptosis
What is structural-based drug development?
Using GPCR structures to design ligands with high specificity
What is the significance of GPCR signaling from endosomes?
It adds complexity by enabling sustained signaling
How do GPCRs signal from internal membranes like mitochondria?
Through constitutively expressed receptors on these membranes
What technique was used to demonstrate GPCR endosomal signaling?
Fusion of GFP to GPCRs to track receptor internalization
What was shown by parathyroid hormone receptor studies?
Sustained cyclic AMP signaling from internalized receptors
Why is endosomal signaling a challenge for drug design?
Drugs must be membrane-permeable to affect internalized receptors
How do biased agonists benefit therapeutic design?
They target specific pathways, minimizing off-target effects
What is an example of a GPCR-targeted drug?
Metoprolol, a beta-blocker used in heart failure
What is the relevance of GPCR complexity to drug development?
It requires consideration of cross-talk and pathway specificity
What is the therapeutic goal of β-arrestin biased ligands?
To provide cardioprotection while minimizing adverse effects
How does ligand-induced GPCR conformation affect signaling?
Different ligands stabilize unique receptor conformations
What is the role of water displacement in ligand binding?
It stabilizes ligand-receptor interactions energetically
What is a major challenge in translating animal GPCR research to humans?
Species-specific receptor isoform differences
