Flashcards in Session 6 Deck (23):
What is a receptor?
A molecule that recognises specifically a ligand or family of molecules and brings about the regulation of a cellular process
What are acceptors?
Molecules that operate in the absence of a signalling molecule (receptors are silent at rest)
What is a ligand?
Any molecule that binds specifically to a receptor site
What are the differences between a receptor binding site and an active site of an enzyme?
Receptor sites have a higher affinity for ligands than the enzyme does for substrates. (Dissociation constant lower than the michaelis constant)
The ligand is not chemically modified
What are common mechanisms membrane bound receptors transduce an extracellular hydrophilic signal into an intracellular event?
Agonist binding produces a conformational change which activates:
Integral ion channels
Integral enzyme activity
Coupling to effectors via transducing proteins
What is the structure of the classic ligand gated ion channel family and examples?
Pentameric subunit structures, each with 4 transmembrane domains, one of which forms the pore. GABA receptor, nAChR and glycine receptors
Give examples of receptors with integral enzyme activity and describe how they work
Growth factor receptors for insulin, epidermal growth factor receptors and PDGFR are directly linked to tyrosine kinase.
The activated tyrosine kinase autophosphorylates tyrosine residues on the cytoplasmic domain of the receptor. These are then recognised either by transducing proteins or directly by enzymes containing tyrosinephosphate recognition sites.
Give examples of GPCRs and describe their structure.
These are 7 transmembrane domain receptors that couple to effector molecules via a guanine nucleotide binding protein (G protein). Effectors may be enzymes or ion channels.
Examples include mAChR, adrenoreceptors, dopamine receptors, opioid receptors and smell & taste receptors.
Discuss intracellular receptors
Hydrophobic ligands such as steroid and thyroid hormones penetrate the plasma membrane and bind to monomeric receptors in the cytoplasm or nucleus.
In their resting state these receptors are stabilised by association with heat shock or chaperone proteins.
The activated receptor dissociates from the stabilising protein and translocates to the nucleus, regulating gene expression. These effects are relatively slow in onset.
Explain amplification in cellular signalling
By stimulating the activity of an enzyme the binding of a chemical signal molecule to a single receptor can cause modification of hundreds/thousands of substrate molecules. An enzymatic cascade can produce further amplification.
Give two examples where receptor activation can lead to cellular activation or inhibition, depending on the receptor.
Increasing or decreasing heart rate through the action of B1 or M2 receptors in cardiac pacemaker cells.
Glycogen breakdown or synthesis in hepatocytes via glucagon or insulin.
What is phagocytosis?
Phagocytosis is the internalisation of particulate matter in specialised cells, which is then degraded.
What is pinocytosis?
Pinocytosis is the invagination of the plasma membrane to form a lipid vesicle. This permits the uptake of impermeable extracellular solutes and the retrieval of plasma membrane. There are two forms: fluid phase and receptor mediated endocytosis.
What is receptor mediated endocytosis?
The selective uptake of substances into the cell by binding to specific cell surface receptors.
Describe the uptake of cholesterol
Cells requiring cholesterol synthesise LDL receptors that recognises apoprotein B. These receptors are localised in clusters over clathrin coated pits that invaginate and pinch off the plasma membrane to form coated vesicles to internalise the LDL particle.
The vesicles are uncoated and fuse with larger vesicles called endosomes.
The pH of the endosome is lower (maintained by an ATP dependent proton pump) than the cytoplasm. The LDL receptor now has a low affinity to the LDL particle and the two dissociate.
The receptors are recycled to the plasma membrane in vesicles and the endosomes containing the LDL particle fuse with lysosomes where cholesterol is released from cholesterol esters.
What is the other name for an endosome?
The compartment for the uncoupling of receptor and ligand (CURL).
How can mutations of LDL receptors lead to hypercholesterolaemia?
Receptor deficiency - no expression of the LDL receptor gene
Non functional receptor - mutation in the LDL binding site
Receptor binding normal - mutation in the c terminal cytoplasmic domain of the receptor that normally interacts with the coated pits. The LDL receptors are distributed over the whole surface of the cell.
Describe the formation and uncoating of coated vesicles.
Coated pit formation is spontaneous. The minimum structure that can be formed is a TRISKELION containing clathrin and light chains. Triskelions associate to form a basket-like structure of hexagons and pentagons.
Uncoating is driven by an ATP dependent uncoating protein. The clathrin coat is then relocated over the pit.
Describe the uptake of Fe3+ ions by transferrin
Two Fe3+ ions bind to apotransferrin to form transferrin in the circulation. This binds to a transferrin receptor at a neutral pH which in internalised in a similar way to LDL. Fe3+ ions are released in the acidic endosome but apotransferrin remains bound to the transferrin receptor. The complex is recycled back to the membrane where at pH 7.4 they dissociate.
Describe the uptake of insulin receptors
Insulin receptors only congregate over clathrin coated pits when they are bound to insulin.
Insulin remains bound to the receptor in the endosome and the complex is sent to lysosomes for degradation.
This reduces the number of receptors on the membrane surface, desensitising the cell to continued high circulating insulin.
Explain transcytosis and give examples
Ligands can remain bound to their receptor and transported across the cell. Examples include maternal immunoglobulins to the foetus via the placenta and transfer of IgA from the circulation to bike in the liver.
During transport of IgA, the receptor is cleaved resulting in the release of IgA with a bound secondary component derived from the receptor.
Summarise the fate of the receptor and ligand in RME of LDL, transferrin, insulin/EGF and maternal IgG/secretory IgA
LDL - receptor recycled, ligand degraded (metabolite uptake)
Transferrin - receptor and ligand recycled (metabolite uptake)
Insulin/EGF - receptor and ligand degraded (down regulation)
Maternal IgG/secretory IgA - receptor and ligand transported