GPCRs Flashcards
What is a GPCR?
G-coupled protein receptor
What is a 7TM receptor?
7 Transmembrane receptor, it crosses the membrane 7 times
What binds to a 7TM receptor and where?
ligand, outside the cell
What activates the G protein?
Binding of a ligand
Where are the G proteins found on 7TM receptors?
On the inside of the membrane
What are 7TM receptors involved in?
neuronal signalling, vision, smell, taste
What receptors are the key target for drugs? And what percentage?
7TM receptors, approximately >30% of drugs target GPCRs
What are the effects of different 7TM receptors based on?
By which G-proteins alpha subunit they activate
Outline the key points in GPCR signalling
- Ligand binds to 7TMR
- 7TMR changes conformation resulting in activation of G protein
- G protein dissociates from 7TMR, G-alpha-GTP and G-beta-gamma are the active forms formed.
- G-alpha-GTP binds to effector proteins.
- G-beta-gamma activates ion channels along membrane.
- GTP is hydrolysed to GDP, G-alpha is no longer active and rebinds to G-beta-gamma
What happens in the activation of the G protein
GDP dissociates from G-alpha and GTP binds. G-alpha-GTP splits from G-beta-gamma
What happens after effectors are activated by G-subunits
They go on to activate other proteins which leads to signal cascades and amplification
Which has a faster response: ligand-gated ion channels or GPCRs
Ligand-gated ion channels
Why are GPCRs slower than ligand-gated channels?
The proteins have to move around in the cell to activate the effectors
Why can you get inverse agonists for GPCRs but not ligand-gated channels?
GPCRs appear to have some activity even without a ligand present, therefore inverse agonists are able to reduce this activity without being ‘negative’
What is basal activity?
Biological response without a ligand being bound to a GPCR
What are 2 factors of drugs that are being improved upon?
Increasing selective targeting, reduce off-target effects
What are the 3 GPCR second messenger pathways?
Gs, Gi and Gq
What does the effect of adrenergic receptors depend on?
The g-protein that it is coupled to and the identity of the tissue that the receptor is found in
Outline the Gq signalling pathway
Receptor and g-protein is activated. This activates Phospholipase C (PIP2 is converted to IP3 and DAG). The increase in IP3 increases concentration of Ca2+ ions = smooth muscle contraction
Outline the Gi intracellular signalling pathway
Receptor and g-protein is activated. The enzyme adenylyl cyclase is inhibited (ATP no longer forms cAMP) = less smooth muscle contraction. Production of Ca2+ is inhibited = inhibition of transmitter release
Outline the Gs intracellular signalling pathway
Receptor and g-protein is activated. the enzyme adenylyl cyclase is activated (ATP forms cAMP) = heart muscle contraction, smooth muscle contraction) and glycogenosis
Which receptors follow the Gi pathway?
Alpha-2
Muscurinic 2 and 4
Which receptors follow the Gq pathway?
Muscurinic 1 and 3
Alpha-1
Which receptors follow the Gs pathway?
Beta-1
Beta-2
