MR S6 - Receptors & Membrane Turnover Flashcards
State a few roles of receptors
Signalling via: Hormones Neurotransmission Cellular delivery Ect
What is a receptor?
A molecule which specifically binds to another molecule to illicit a change in a cellular process
What is a ligand?
Any molecule that binds specifically to a receptor site
What is an agonist?
A ligand which binds to a receptor and causes activation of that receptor
What is an antagonist?
A ligand which binds to a receptor and doesn’t cause activation of that receptor
What is signal transduction?
The transmission of a signal inside the cell when a ligand binds to a receptor on the cell surface
How may a signal be transduced?
- Integral ion channels
- Integral enzyme activity
- Coupling to effectors through transducing proteins
Why is signal transduction necessary?
To propagate the signal within the cell - hydrophilic ligands cannot pass the cell membrane so signal transduction is required
Describe membrane transduction by integral ion channels
Agonist binding causes conformational change and the opening of a gated channel
Channel then permits the movement of ions down their concentration gradient
Eg classical nAChr and non classical Ryanodine receptors
Describe membrane receptors with integral enzyme activity
Agonist binding to the extracellular domain causes conformational change
This activates an enzyme which form a part of the protein structure
Eg PDGF and linked tyrosine kinase
Describe tyrosine linked receptors
Autophosphorylate upon ligand binding
Residues recognised by transducing proteins or directly by enzymes
Upon association, effector enzymes are activated which transduce the message into an intracellular chemical event
Eg insulin receptor
Describe membrane bound receptors with transducing proteins
This family of receptors are known as GPCRs
7 transmembrane domain receptors couple to effector molecules via a transducing protein: a GTP binding regulatory protein or G protein
Effectors may be enzymes or ion channels
What is integrated signalling?
When separate GPCRs act simultaneously to stimulate or inhibit an effector
The two inputs combine to produce a measured effect
Give examples of GPCRs
Dopamine receptors, mAChR, 5-HT receptors and light, smell and taste receptors
Describe the specificity of GPCRs in relation to their distribution
Very specific
Several GPCRs can exist for the same agonist
Eg M1-5 ACh receptors - each type are found in different locations.
Useful as drugs can be targeted at one type of GPCR to only affect a local area.
Give examples of hormones with intracellular receptors
Hydrophobic hormones eg: Oestrogen Testosterone T3 & T4 Cortisol
Describe binding to intracellular receptors
Hydrophobic ligands pass through the cell membrane
Bind to intracellular receptors (in resting state these are bound to heat shock or chaperone proteins)
Activated receptor dissociates from it’s stabilising protein and moves to the nucleus where it binds to control regions in DNA
What is a disadvantage of intracellular receptors?
They bind to DNA so they change translation and/or transcription therefore they have a slower effect than extracellular receptors
How does amplification of signalling molecules occur?
Many ways eg
Stimulation of an enzyme can cause the binding of a single molecule to be amplified to hundreds or thousands of molecules
Enzyme cascades can be triggered, causing further amplification
Why may amplification of cellular signals be necessary?
The concentrations of extracellular signalling molecules can be very low so amplification may be needed to trigger an appropriate response
In cardiac pacemaker cells, stimulation of which receptors cause increase and decrease of heart rate?
Increase: β1 adrenoreceptors are activated by noradrenaline
Decrease: M2 muscarinic receptors are activated by acetylcholine
In hepatocytes, how does hormonal stimulation affect glycogen stores?
Insulin binding to receptors stimulates glycogen synthesis
Glucagon binding to receptors stimulates glycogen breakdown
Describe phagocytosis
A particle binds to a receptor on the cell membrane
The cell extends pseudopods to invaginate the particle with a membrane zippering mechanism
Internalised phagosomes fuse with lysosomes to form phagolysosomes in which the particle is degraded
What is pinocytosis?
The invagination of the plasma membrane to form a lipid vesicle
Permits uptake of impermeable extracellular solutes and retrieval of plasma membrane
Sub divided into fluid phase and receptor mediated endocytosis (RME)
Describe receptor mediated endocytosis (RME)
Specific binding of molecules to cell surface receptors permits the selective uptake of substances into the cell
Describe the uptake of cholesterol as an example of RME
LDL binds to apoprotein B receptor in clathrin pit on target cell surface
Pit invaginates to form coated vesicles
Coated vesicles are actively (aka using ATP) uncoated
They then fuse with endosomes
LDL particle and receptor dissociate
Receptor is recycled and returns to plasma membrane
Endosome fuse with lysosomes
Cholesterol is hydrolysed from the esters and released into the cell
Describe the structure of an LDL
Core of fatty acids (esterified cholesterol)
Lipid mono layer of phospholipids, cholesterol and apoprotein B
How is cholesterol only absorbed by cells that require it?
The target cells have apoprotein B receptors located in clathrin coated pits which spontaneously form on the cell membrane
These pits cover ~2% of the cell surface
Why do the LDL receptors and particles dissociate in the endosome?
The pH is lower within the endosome than in the cytoplasm (5.5-6.0)
This means the receptor and particle have a lower affinity for each other
What is an endosome also known as and why?
A CURL
Compartment for the Uncoupling of Receptor and Ligand
This is where the receptor and ligand uncouple
What are the different ways the LDL receptor can be affected in hypercholesterolaemia?
Non-functioning receptor
C-terminal mutation
Receptor deficiency
What would be the effect of a mutation to the binding site of an LDL receptor?
A mutation in the binding site could change the conformation so the receptor can no longer bind to the LDL so no uptake of LDL therefore LDL receptor os non functional
What would be the effect of a mutation to the C-terminal of an LDL receptor?
The receptor interacts with clathrin with it’s c terminal domain
If there is a deletion of the C-terminal domain, the receptor can’t interact with clathrin
Therefore the receptors will be spread out across the membrane instead of in the 2% of the membrane where there are clathrin pits
How may a receptor deficiency be caused?
By a mutation which prevents expression of the LDL receptor
Eg a start codon deletion
Describe the uptake of Fe3+ ions as an example of RME
Two Fe3+ ions bind to apoptransferrin to form transferrin in the circulation
Transferrin binds to it’s receptor on the cell surface
Upon reaching the acidic endosome, the Fe3+ ions release
The complex is sorted for recycling back to the plasma membrane where the apoptransferrin dissociates from the receptor
Why does the receptor-apoptransferrin complex only dissociate at the membrane?
Affinity at neutral pH is greatly reduced so it is only at the membrane that the apoptransferrin dissociates from the receptor
Describe the uptake of occupied insulin receptors
When occupied, the insulin receptors gather over clathrin pits
Upon insulin binding, the pit invaginates to form a coated vesicle
The vesicle is actively uncoated and fuses with an endosome
At the endosome, the insulin-receptor complex remains associated
The endosome fuses with a lysosome and both ligand and receptor are degraded
What are the three steps of RME that are common to all examples?
Pit invaginates to form coated vesicles
Coated vesicles are actively (aka using ATP) uncoated
They then fuse with endosomes
What is the importance of insulin and it’s receptor remaining associated in the endosome?
The mechanism allows for a reduction in the number of receptors on the cell surface
This desensitises the cell to constant high circulating insulin
What is transcytosis?
When ligands remain attached to their receptors and are transported across the cell
Eg maternal immunoglobulins are transferred to the foetus
Eg immunoglobulin A is transported from the circulation to bile in the liver
What are the modes of RME?
1-Where the receptor is recycled and the ligand degraded
2-Where both the receptor and the ligand are recycled
3-Where both the receptor and the ligand are degraded
4-Where both the receptor and the ligand are transported
Give an example and describe the function of a ligand involved in mode 1 of RME
Ligand: LDL
Function: metabolic uptake
Give an example and describe the function of a ligand involved in mode 2 of RME
Ligand: transferrin
Function: Fe3+ uptake
Give an example and describe the function of a ligand involved in mode 3 of RME
Ligand: Insulin
Function: Metabolic control
How do membrane-enveloped viruses and toxins take advantage of RME? Give examples
Once in the endosome, the acidic pH allows the viral membrane to fuse with the endosomal membrane, releasing toxins or viral RNA into the cytoplasm
Eg the diphtheria and cholera toxins, both of which bind to the GM1 ganglioside
Give an example and describe the function of a ligand involved in mode 4 of RME
Ligand: maternal IgG, IgA
Function: transfer of large molecules across a cell
