Full & Partial Agonists (Lecture 10) Flashcards
What is the difference between full & partial agonists?
Full agonists - can produce a MAXIMAL tissue response
Partial agonists - cannot produce a maximal tissue response, regardless of how high their concentration is
What is meant by agonist efficacy ?
The ability of the agonist to stabilise the active state of the receptor
I.e. AR <—> AR*
What is the Del Castillo model of receptor activation, and what does it take into account?
Takes into account the activation of the receptor:
Step 1 (k+1): Binding of the agonist, equilibrium constant
A + R <—> AR
Step 2 (E): Conformational change to an active state
AR <—> AR*
What are the full and partial agonists of B-adrenoreceptors?
Full - adrenaline, isoprenaline
Partial - prenalterol
What are the full & partial agonists of Histamine H2 receptors?
Full - histamine
Partial - impromidine
What are the full & partial agonists of beta-adrenoreceptors?
Partial - prenalterol
Full - adrenaline, isoprenaline
What are spare receptors and why are they important?
Tissues have ‘spare receptors’ - more receptors than needed to produce a maximum response (i.e. if sufficient ion channels are open to fully depolarise a cell, opening more won’t give a bigger response)
The number of spare receptors is important with a partial agonist as this determines the maximum response - a partial agonist for one tissue could act as a full agonist for another if there is a large enough number of receptors
What is desensitisation?
Tissue response decreases despite continued presence of agonist
How can desensitisation happen?
Agonist-bound ligand gated ion channels in the activated state (AR*) can isomerise to an inactive, desensitised state
Phosphorylation of receptors on GPCRs by one or more protein kinases (activated by agonist binding) can be followed by a loss of some receptors from the cell surface
What does comparing the effect of:
1. Increasing concentrations of partial agonists on tissue response
2. A fixed concentration of full agonist on tissue response
Show?
That the partial agonist is able to combine with all the receptors, provided it has a high enough concentration, however the tissue response is less than when using a full agonist
Partial agonist reaches submaximal response, then plateaus as concentration increases - shows that it won’t reach the maximal response produced by the full agonist
What does adding low concentrations of a full agonist to a partial agonist show?
Increases the response but concentration-response curves will cross as [full agonist] is increased.
This is because the presence of the partial agonist reduces the number of available receptors (to the full agonist) - therefore the partial agonist reduces the response to the full agonist
What 2 ways can we rule out the explanation that partial agonists have a smaller effect because they are not able to combine with all of the receptors?
- Comparing the effect of increasing the concentrations of a partial agonist on tissue response, with the tissue response with a fixed concentration of full agonist
- Adding low concentrations of a full agonist to a partial agonist
Why are some agonists (i.e. full agonists) better able to stabilise the active receptor conformation than others?
Due to bonds / interactions they make with the receptor
What is the difference between a partial & full agonist?
Their ability to ACTIVATE (rather than bind to) the receptor
In a partial agonist, AR —> AR* rate may be slow, but AR* —> AR will be faster as there are fewer bonds holding it in the active state
What are Slow-Channel Congenital Myasthenic Syndromes (SCCMS) and what are they characterised by?
Disorders of neuromuscular transmission
Characterised by muscle weakness & fatiguability (caused by degeneration of the junctional folds)
Mutations cause prolonged endplate currents - shown by changes in both the binding & efficacy of ACh
What is the difference between what would be shown by a healthy ‘wild type’ channel and an SCCMS mutant channel? (On the line graph thing)
Healthy ‘wild type’ channel - mostly closed but opens in bursts when ACh is bound
SCCMS mutant - channel is open for a longer time - difference in ACh efficacy & binding
What are the characteristics of a negative / inverse agonist for a constitutively active receptor?
A + R (inactive) —-> AR (inactive)
- doesn’t cause a conformational change to the receptor
- only combines with inactive receptors (R)
- promoting the formation of (inactive) AR
- thus reducing the proportion of active receptors (R*)
What are the characteristics of a conventional agonist for a constitutively active receptor?
Constitutively active receptor: R (inactive) <——> R* (active)
- conventional agonist only combines with active receptor (R*)
- promoting the formation of (active) AR* (A + R* <—-> AR*)
What are the characteristics of a reversible competitive agonist for a constitutively active receptor?
Constitutively active receptor: R (active) <—> R* (active)
- reversible comp agonist doesn’t cause a conformational change to the receptor
- has equal affinity for both R & R*
A + R —> AR
A. R* —> AR* - therefore doesn’t affect the proportion of receptors in the active R* state
What are constitutively active receptor?
Receptors which activate in the absence of agonist - random collisions can provide enough thermal energy for the receptor to assume the active conformation
R(inactive) <—> R* (active)
Describe receptor activation (agonist efficacy)
- receptors (e.g. GPCRs / ligand-gated ion channels) are activated by agonists binding - which causes a conformational change in the receptor
- on binding, receptors (e.g. H-H bonds / charge-charge interactions) which stabilise the active conformation of the receptor
- this conformational change is reversible, at some point, the receptor-agonist complex will have enough thermal energy to break the bonds holding them in the active conformation
- some agonists (e.g. full agonists) are better able to stabilise the active receptor conformation (AR*) than others (e.g. partial agonists) due to the bonds / interactions they make with the receptor
What is the difference between the dose-response curves for full and partial agonists?
Full agonist - curve saturates at high concentrations - indicating that it has reached its maximum response
Partial agonist - curve reaches a plateau at a lower level than the full agonist, despite increasing concentrations - indicating that it cannot produce the same maximal effect
Where might partial agonists be advantageous over full agonists in treatment?
In situations such as…
- where too much receptor activation may be harmful
- where the desired biological response is less than the maximum possible
What is the different between the efficacy of partial and full agonists ?
Partial agonists have a LOWER EFFICACY than full agonists
