Lecture 6: Membrane function 3 - Membrane receptors Flashcards
Learning Objectives
- Understand the role of cell surface receptors
- Appreciate the function of GPCRs
- Understand the mechanisms of receptor activation and G-protein initiation of signalling events
- Appreciate how GPCRs and G-protein re-set after activation
How is a receptor different to a transporter?
In a receptor there is no movement of a molecule from one side of the membrane to the other, like in a transporter. Instead, the receptor undergoes a conformational change when bound to by a ligand, which relays information by causing a response on the other side of the membrane, normally inside a cell or organelle.
Which stimuli can activate a receptor?
Neurotransmitters, hormones, light, odorants, drugs
What are the three types of receptor?
- Ion-channel coupled receptors (ions are transported, ligand is not transported)
- Enzyme-coupled receptors (the binding of the ligand brings two parts of the receptor together, forming an active catalytic region or a platform for an enzyme to be activated by.
- G-protein coupled receptors (the binding of the ligand causes the receptor to activate the G-protein, which in turn activates a membrane-bond enzyme)
Describe the structure of the receptor part of G-protein coupled receptors?
The amino terminal is extracellular and the carboxyl terminal is intracellular. There are 7 transmembrane domains. They are a bundle of a-helices.
Are G-protein coupled receptors high or low affinity?
High affinity receptors, which means they can detect very small amounts of the ligand.
Describe the structure of a G protein.
G proteins are heterotrimers: they are made up of 3 different subunits (alpha, beta, gamma). The alpha and gamma subunits are lipid-modified and anchored to the membrane (localising them where the receptors are). The beta subunit is the mediator between the two. The alpha subunit can bind GTP or GDP. G-proteins are specific to the receptor. There is a range of G-proteins with different downstream effects when activated.
How are G proteins activated?
A ligand binds to the extracellular part of the receptor, causing a conformational change of the receptor. This conformational change causes a conformational change the G protein and affinity of the alpha subunit for GDP drops and the affinity for GTP rises. This causes the alpha subunit to exchange GDP for GTP. The alpha subunit then dissociates from the rest of the G protein (the beta-gamma dimer) and diffuses along the membrane to an enzyme (e.g. adenylate cyclase), which it activates.
What is the structure of adenylate cyclase?
It has 12 transmembrane domains and 2 extended soluble regions on the cytoplasmic side, which is where the alpha-GTP complex binds, which causes a conformational change in adenylate cyclase. This conformational change causes adenylate cyclase to favour conversion of ATP to cAMP.
What are the downstream signalling effects of cAMP?
cAMP is released when adrenaline binds to the receptor. The body then prepares for ‘fight or flight’.
- Increased ATP production
- Increased degradation of fuel stores
- Reduced aggregation of platelets
- Opens chloride channels
- Protein expression increased/decreased in the nucleus
How is a G protein deactivated?
Alpha subunits have GTPase activity, meaning that it spontaneously hydrolyses GTP to GDP. This is a slow reaction. The alpha subunit then spontaneously re-associates with the beta-gamma dimer to give the inactive heterotrimer molecule.
How is a receptor deactivated?
The ligand dissociates slowly (due to high affinity). However, another ligand could bind easily due to the high affinity, so the arrestin protein binds to phosphorylated Serine/Threonine in the cytosolic tail of the receptor. This prevents further association of the G protein heterotrimer by blocking the G protein binding site.
Why are G protein coupled receptors so important?
- They control a vast number of key cellular processes
- Almost 50% of all prescribed drugs act through G protein coupled receptors.
