Receptor-Effector Coupling Flashcards
What are 2 biological approaches to receptor classification?
- Molecular structure
2. Signal transduction mechanism
What 3 things affect the molecular structure of receptor proteins?
- Amino acid sequence
- 2ry and 3ry structure
- Location of binding sites
What 3 things affect the signal transduction mechanism?
- Ion flux
- Enzyme activity
- Gene expression
How many super families of receptors are there?
4
Name the 4 receptor super families
- Ligand-gated ion channels
- G-protein-coupled receptors
- Kinase-linked receptors
- Nuclear receptors
What is the major differences between families 1-3 and family 4?
First 3 families are on cell surface whereas nuclear receptors are intracellular
What causes a group of receptors to become a superfamily?
Possess basic molecular and functional properties as each other but encoded by different genes which causes different shapes of receptors which respond to a specific mediator
What 2 substances stimulate superfamily 1 receptors?
- Acetylcholine
2. Nicotine (selectively)
Name 2 competitive reversible antagonists to superfamily 1 receptors
- Tubocurarine
2. Vecuronium
Name a non-competitive antagonist to superfamily 1 receptors
Lidocaine
What is the function of neuromuscular blocking agents such as tubocurarine?
Prevent skeletal muscle contraction during surgery
How does lidocaine act as a non-competitive antagonist to superfamily 1 receptors?
Antagonises the action of acetylcholine at some point in the chain
What are 3 characteristics of nicotinic cholinoceptors in neuromuscular junctions?
- Receptor is made up of 5 sub-units
- Primary amino acid sequence runs from N terminal to C terminal
- 4 transmembrane helices allow sub-unit to move through membrane and be anchored
- 2nd helix of each sub-unit comprise the channel pore
How is a nicotinic receptor activated?
A molecule of acetylcholine must bind to both a sub-units in the receptor
What are 3 characteristics of receptors in superfamily 2?
- Single protein spans 7 times across membrane to anchor it
- Extracellular N terminal binds to substances
- Cytoplasmic and extracellular loops found between different parts of protein spanning membrane
What are receptors in superfamily 2 coupled with?
Heterotrimeric G-proteins
What are 3 characteristics of a G-protein?
- Consist of 3 sub-units (alpha, beta, gamma)
- Molecular switches
- Communicate between superfamily 2 receptor and an effector
What 3 sites are found on the a sub-unit of a G-protein?
- Receptor interaction site
- GTP binding site
- Target protein interaction site
Describe the switching on and off of G-proteins
- GTP binds to the a subunit which turns on G-protein
- Intrinsic enzyme activity of GTPase breaks down GTP bound to sub-unit
- GTP broken down to GDP which is released from a sub-unit as the reaction stops
What is a second messenger?
Intracellular chemical, the concentration of which can be altered rapidly and reversibly on activation of a cell surface receptor, to regulate activity of an internal effector to produce intracellular response
What are the 2 mechanisms which second messengers generally come about?
- G-protein activates ion channel which allows ion to accumulate
- G-protein activates enzymes which generate ions
What can regulate concentration of ions acting as second messengers?
Internal effector
What gives G-proteins specificity?
Different a sub-units are encoded by a different gene or splice variants
How can G-proteins be stimulator or inhibitory?
Can induce a conformational change in effector protein to more or less active states
Give 3 examples of effectors regulated by G-proteins
- Adenylate cyclase
- Phospholipase C-b
- Voltage-gated calcium/potassium channels
Describe cyclic AMP signalling pathway
- Noradrenaline or adrenaline activates G-protein
- Enhanced binding of GTP activates G-protein
- Interaction with adenylate cyclase which catalyses production of second messenger
- Second messenger regulates cAMP-dependent protein kinase
- Kinase catalyses protein phosphorylation to bring about cellular response
Name 2 types of drugs and their function which target cyclic AMP signalling pathway
- β₁ adrenoceptors - Enhance cardiac muscle action
2. β₂ adrenoceptors - Bronchodilation
What is an example of a β₁ adrenoceptor drug?
Dobutamine
What is an example of a β₂ adrenoceptor drug?
Salbutamol
Name an antagonist drug of β₁ adrenoceptors
Beta blockers e.g. atenolol
What are 3 ways a cyclic AMP signalling pathway can be terminated?
- Breaking down the mediator
- Breaking down GTP
- Metabolism for cAMP in cytoplasm
How is cAMP metabolised in cytoplasm?
Enzyme cyclic AMP phosphodiesterase hydrolyses across ring leading to linear molecules which does not activate kinase
How does caffeine lead to a greater response of cyclic AMP signalling pathway?
Inhibits the action of cAMP phosphodiesterase
What are 2 types of superfamily 3 receptors?
- Receptors directly linked to tyrosine kinase
2. Receptors directly linked to guanylate cyclase
Name 4 receptors which are directly linked to tyrosine kinase
- Insulin
- Insulin-like growth factor
- Epidermal growth factor
- Cytokine
Name 2 receptors which are directly linked to guanylate cyclase
- Natriuretic peptide
2. Guanylin
What is the function of tyrosine kinase?
Phosphorylates tyrosine amino acids into proteins
What is the function of guanylate cyclase?
Creates cyclic GNP
Describe the 5 steps of activation and transduction of tyrosine kinase-linked receptors?
- Ligand binds to receptor which causes conformational change in receptor
- Dimer forms
- Dimer formation increases enzyme activity
- Enzyme phosphorylates tyrosine groups on adjacent molecule in the dimer
- Dimer splits
What is the function of SH-2 domain protein?
Recognize the phosphorylated amino acids in which phosphorylation helps binding of proteins to enzymes
Give an example of a drug which targets tyrosine kinase-linked receptors
Herceptin
How does herceptin slow tumour progress
Bind to proteins which prevents receptors from binding with growth factors and slowing tumour progress
Name 3 types of receptors in uperfamily 4
- Receptors for lipophilic steroid hormones
- Receptors for lipid mediator present in cells
- Receptors for lipophilic vitamins
Describe the mechanism of action of superfamily 4 receptors
- Agonist binds to intracellular receptors
- Zinc finger domain opens and binds to hormone responsive elements
- Activity of RNA polymerase, gene transcription and translation of mRNA is affected
- This allows synthesis of new proteins and altered cellular reponse
Name 2 type of nuclear receptor therapeutics
- Aldosterone receptor antagonists e.g. spironolactone
2. Corticosteroid receptor agonists e.g. budesonide
