Receptors Flashcards
How are receptors classified?
Primarily by specificity to a physiological signalling molecule, divided further on the basis of their affinity to a series of antagonists.
Define receptor
A molecule that recognises specifically a specific second molecule or family of molecules and in response to binding brings about the regulation of a cellular process.
By definition they are silent at rest, if it operates in absence of a ligand it is an acceptor
Give 3 roles of receptors
Signalling via hormones, neurotransmitters and cellular delivery (eg LDLs and transferrin)
Define ligand
Any molecule that binds specifically to a receptor site
Define agonist
A ligand that produces the activation of a receptor when it binds
Define antagonist
A ligand that binds to a receptor without causing activation
Why is signal transduction necessary for some signalling molecules?
Hydrophilic signalling molecules cannot pass through the membrane, unlike hydrophobic signalling molecules.
How can membrane bound receptors accomplish signal transduction?
Via:
- Integral ion channels
- Integral enzyme activity
- Coupling to effectors via transducing proteins
How do membrane bound receptors with integral ion channels work?
Agonist binding results in a conformational change and the opening of a gated channel. The channel then permits the glow of ions down an electrochemical gradient.
What’s the structure of the classical family of integral ion channels?
Pentameric subunit structures with four transmembrane domains.
Give examples of classical and non-classical integral ion channels
Classical: nAChR, GABA, glycine receptor
Non-classical: Ryanodine receptor, ATP-sensitive K channel, IP3 receptor
How do membrane bound receptors with integral enzyme activity work?
Agonist binding to extracellular domains causes a conformational change, which activates integral enzyme activity within the protein structure of the receptor eg tyrosine kinase linked receptors
How do tyrosine kinase linked receptors bring about a response within the cell?
They autophosphorylate on receptor binding,
Phosphorylated receptor tyrosine residues are recognised by transducing proteins or directly by enzymes containing phosphotyrosine recognition sites (Src-homology-2 domains).
Effector enzymes are activated allosterically/by tyrosine phosphorylation by the receptor kinase.
This transduces the message into an intracellular chemical event.
Give examples of membrane bound receptors with integral enzyme activity
Insulin receptor
Epidermal growth factor receptor
Platelet derived growth factor receptor
How do membrane bound receptors with transducing proteins work? (GPCRs)
Seven transmembrane domain receptors (7TMDR) couple to effector molecules via a transducing molecule, a GTP-binding regulating protein (G-protein).
Effectors may be enzymes or ion channels
Give examples of G-protein coupled receptors
mAChR
Dopamine receptors
5-HT receptors
Light, smell and taste receptors
What is the full name for a G-protein?
GTP-binding regulatory protein
What is integrated signalling?
Where separate G-protein coupled receptors act simultaneously to both stimulate/inhibit the effector.
The two inputs combine to produce a measured effect.
What type of ligands bind to intracellular receptors?
Hydrophobic ligands
Give examples of hydrophobic ligands
Steroid hormones
Thyroid hormones
How do intracellular receptors work?
They are bound to heat shock or chaperone proteins, dissociate when the ligand binds.
They translocate into the nucleus and bind to control regions in DNA, regulating gene expression.
Why is the action of intracellular receptors relatively slow?
They are dependent on transcription and translation
Give 2 examples of how responses to different receptors can lead to cellular activation/inhibiton
In cardiac pacemaker cells:
NA binding to B1-adrenoceptors increases heart rate, ACh binding to M2-muscarinic receptors decreases heart rate.
In hepatocytes:
Insulin stimulates glycogen synthesis from glucose
Glucagon stimulates glycogen breakdown to glucose
Describe the process of phagocytosis
In response to a particle binding to receptors the cell extends pseudopods that permit further receptor interactions and membrane invagination via a ‘membrane zippering’ mechanism.
Internalised phagosomes fuse with lysosomes to form phagolysosomes where the particle material is degraded.
Describe the process of pinocytosis
The invagination of the plasma membrane to form a lipid vesicle.
Permits the uptake of impermeable extracellular solutes and retrieval of plasma membrane.
What are the 2 forms of pinocytosis?
Fluid-phase
Receptor Mediated Endocyotosis
What is Receptor Mediated Endocyotosis (RME)?
The specific binding of molecules to the cell surface permitting the uptake of substances into the cell
Describe uptake of cholesterol by receptor mediated endocytosis
LDL receptors are localised in clusters over Clathrin coated pits, these recognise ApoB on the LDL protein
The pit invaginates to form coated vesicles. The vesicles are uncoated (requires ATP) and fuse with endosomes.
The LDL and its receptor dissociate in the low pH (the endosome is the CURL)
Receptor buds off in a vesicle and is recycled to the membrane, the endosomes fuse with lysosomes, cholesterol is hydrolysed from the esters and released into the cell
What are endosomes and how do they maintain a low pH?
Endosomes are large smooth vesicles, the low pH (5.5-6) is maintained by an ATP-dependent proton pump.
The endosome is also known as the Compartment for the Uncoupling of the Receptor and Ligand (CURL)
Describe the different mutations effecting the LDL receptor in hypercholesteraemia
- Non-functioning receptor: mutation in LDL binding site prevents uptake
- Receptor binding normal: deletion in C-terminal domain prevents interaction between receptors and the Clathrin coat, so receptors are distributed across whole surface not concentrated.
- Receptor deficiency: mutation that prevents expression of LDL receptors
Describe the uptake of Fe ions by transferrin by receptor mediated endocytosis
Two Fe ions bind to apotransferrin in circulation to form transferrin, binds to transferring receptors localised in clusters over Clathrin coated pits.
Pit invaginates forming a coated vesicle and is uncoated using ATP. Binds with endosome and Fe ions dissociate at the low pH but apotransferrin remains associated.
Complex is sorted in the CURL for recycling back to membrane where at normal pH the apotransferrin dissociates from receptor.
Describe the uptake of occupied insulin receptors by receptor mediated endocytosis
Receptors only congregate over Clathrin coated pits when their agonist is bound (binding induces conformational change that allows recognition by pit).
Pit invaginates and is uncoated using ATP, binds to endosome.
In the endosome insulin remains bound and is targeted to lysosomes for degradation (receptor not recycled).
Means number of receptors on membrane is reduced, desensitising cell to continued high circulating insulin.
Explain transcytosis
Transportation of ligands bound to receptors across the cell.
Give examples of transcytosis and explain
Transfer of maternal immunoglobulins to the foetus via the placenta.
Transfer of immunoglobulin A from the circulation to bile in the liver.
During transport of IgA the receptor is cleaved, resulting in the release of the immunoglobulin with a bound secretory component derived from the receptor.
Give 2 examples of RME where the receptor is recycled and give the fate of the ligands
- LDLs - ligand is degraded
2. Transferrin - ligand is recycled
Give 2 functions of degrading both the receptor and the ligand in RME
Receptor down regulation
Removal of foreign antigens from the circulation
Give 3 examples of RME where the ligand is degraded and give the fate of the receptors
- Transferrin - receptor is recycled
- Insulin/ epidermal growth factor - receptor is degraded
- Immune complexes - receptor is degraded
What are the 4 modes of receptor mediated endocytosis
- Receptor recycled, ligand degraded, eg LDLs
- Receptor recycled, ligand recycled, eg transferrin
- Receptor degraded, ligand degraded, eg insulin
- Receptor transported, ligand transported, eg maternal IgG
Describe how membrane enveloped viruses and toxins take advantage of receptor mediated endocytosis to gain entry into the cell
They bind to receptors on plasma membrane
Once in the endosome the acidic pH allows the viral membrane to fuse with the endosomal membrane, releasing viral RNA into the cell where it is translated and replicated to form new viral particles.
Give examples of toxins that take advantage of RME to enter the cell
Cholera toxin and Diphtheria toxin
Both bind to GM1 Ganglioside
