Receptor Mechanisms - Albert's lecture Flashcards
Give a review of receptors and the general mechanism of action they follow
- Recognise and bind drugs – endogenous or ‘given’ chemicals
- Provide communication between extracellular and intracellular environments to produce a biological response
Drugs bind to receptor -> Conformational change of receptor -> signal transduction -> cellular response
Describe the 4 properties of receptors
Tissue selectivity – different receptors are found in different areas.
Chemical selectivity – only particular drugs will be able to bind to a receptor, there is structural specificity.
Extracellular/intracellular communication
Amplification – drugs can work at low concentrations, time scale, the application.
What is a transmembrane protein?
They are transmembrane proteins – proteins which can span the membrane, they have areas which are hydrophilic and hydrophobic
What do the amino acids in a receptor compose:
It is the specific sequence of amino acids that compose:
• Structure and Selectivity of drug bound and the structure of the receptor to bind to an agonist, gives it a specific shape like an enzyme.
• Type of intracellular pathways activated – structure determines what process can occur.
• Timescale of information transfer (ms to days) – response can be quick or slow.
Describe and give examples of ligand-gated ion channels and there mechanism of action
.g. Nicotinic receptors - controlling skeletal muscle contraction
e.g Glutamate receptor – controlling action potentials firing in brain
• Ligand-gating receptors composed of five protein subunits
• Subunits form an ion channel
• Ligand-binding site is on the N-terminal region extracellular site
Describe and give an example of G-protein coupled receptor
e.g. β-adrenoceptors in heart 1000s of GPCRs, e.g. smell, taste • 1 Single protein • 7 transmembrane regions (7 spanning) • N-terminal - ligand-binding site • C-terminal - G-protein binding region • There are 3 subunits: a large alpha subunit, beta and gamma. When the receptor is not active GDP binds to the alpha and is held in the membrane by a beta and gamma subunit.
What are G-proteins and what is the mechanism of action they tend to undergo?
Guanine nucleotide (GTP/GDP) binding proteins- composed of 3 subunits: , and . Couple drug-receptor interaction to cellular response.
Lots more G-protein than receptors
Amplification of signal
- No drug bound – G-protein bound to receptor, GDP is bound to subunit
- Drug binding
- Change in receptor conformation
- Now GTP binds to G subunit
- G subunit dissociates from receptor – induces cellular response
- Intrinsic Gα subunit GTPase activity – GTP dephosphorylates to GDP
- G-protein subunits re-associate and bind with unbound receptor
Describe what G-protein alpha subunits determine which reaction in a cell
• Different subtypes of subunits, e.g. Gs, Gi, Gq
• Different subunits interact with specific targets
• Two main targets are adenylate cyclase (AC) and phospholipase C (PLC)
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Describe and give examples of the G-alpha-S and G-alpha-I pathway
Adrenaline will bind to a beta 1 receptor (a type of Gs receptor) and follow this mechanism described below, PKA then increases the firing of action potentials in the heart to increase heart rate.
Gi receptors are muscarinic receptors in the heart which slow down heart rate when acetylcholine binds. PKA is reduced which reduces action potentials in the heart.
Methods of Gs and Gi here:
1. The alpha subunit binds to the adenylate cyclase - this is the effector protein.
2. Once this has bonded the adenylate cyclase it converts ATP (substrate) to cAMP. This cAMP activates an inactive protein kinase to form an active protein kinase. This can then phosphorylate lots of other things. PKA has two subunits, regulatory and catalytic subunit.
3. cAMP binds to the regulatory subunit of PKA, the catalytic subunit dissociates to phosphorylate proteins within the cell
4. Resulting in a series of intracellular events.
- This results in the inhibition of adenyl cyclase.
- The alpha subunit binds to adenyl cyclase. This means that adenyl cyclase is deactivated.
- Other events within the cell cannot occur. This means that ATP cannot be converted to cAMP, to PKA is not activated so there is no phosphorylation of proteins within the cell.
- So, no intracellular events occur
Describe the Gq pathway
- Once the alpha subunit has left the gamma and beta in the lipid phase, it stimulates an enzyme called phospholipase C.
- Phospholipase C works on a membrane protein called PIP2.
- This produces IP3 which moves into the cytoplasm, and DAG is produced.
- So two signalling molecules are produced – IP3 and DAG.
- IP3 binds to a receptor that allows the release of calcium ions out the cell. Well as DAG interacts with its own kinase
Describe the structure and mechanism of action of a tyrosine kinase receptor
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Describe the structure of and mechanism of action of an intracellular protein
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