Receptor Desensitisation

Question 1

What is receptor desensitisation?

Answer 1

It is the tendency of biological responses to diminish over time despite continued presence of a stimulus of constant intensity.

When an agonist is introduced to a system and max response is attained, continuous presence of the agonist will lead to decline in the response of the receptor.
It is usually reversible.

Question 2

What are the types of desensitisation?

Answer 2

i. Homologous desensitisation: agonist-induced desensitisation of a receptor that occurs when the receptor is stimulated only by this particular agonist.
- Only the receptor is affected.
reduced.
May involve:
- Covalent modification of the receptor, e.g. phosphorylation by protein kinase in β-adrenoceptor
- The destruction of the receptor or
- Its relocation within the cell

ii. Heterologous desensitisation: desensitisation of a particular receptor following activation of other receptors in the cell by their respective agonists. May be due to either:
- The modification of each receptor involved by common feedback mechanism or
- Changes effected at some common points in the effector pathway distal to the receptor itself.

Question 3

What is the function of receptor desensitisation?

Answer 3

• It protects cells from excessive or prolonged stimulation.
• It may constitute a mechanism for hormonally mediated regulation of cell differentiation or function in a
  multicellular organism.

Question 4

What are some disease states associated with receptor loss?

Answer 4

i. Myasthenia gravis where the immune system produces antibodies that target the nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ).

ii. Obesity in the context of excessive insulin action that elicits a series of cellular homeostatic responses,
producing systemic insulin resistance:
- homologous desensitisation to insulin action
- leptin secretion
- inflammation
- counter-inflammation phase to conserve energy storage

Question 5

List 6 mechanisms of receptor desensitisation.

Answer 5

1. Active extrusion of drug
2. Physiological adaptation
3. Increased metabolic degradation
4. Change of receptor
5. Loss of receptor
6. Exhaustion of mediator

APICLE

Question 6

Describe the mechanism of β-Adrenoceptor desensitisation.

Answer 6

• After agonist binds to the receptor, the carboxyl terminal tail of the receptor is phosphorylated on the serine or threonine residue by β-adrenergic kinase (βARK)
• The presence of phospho-serine increases the affinity of the receptor to bind to a third protein β-arrestine (β-ARR).
• The binding of β-ARR to the receptor reduces its ability to interact with the G protein, thus reducing the agonist response.
• Upon removal of the agonist, phosphate is removed from the receptor by cellular phosphates and β-ARK cannot add phosphate to the carboxyl end in serine.

Question 7

What is the mechanism of α-adrenoceptor desensitisation.

Answer 7

The mechanisms involved have been shown to include:
- uncoupling of receptors
- downregulation, as well as
- post-receptor alterations.

Question 8

Discuss the mechanism of muscarinic receptor desensitisation.

Answer 8

Mechanisms through which this happens include:
- internalisation
- down-regulation
- uncoupling of the G protein from the receptor, and
- structural changes such
as phosphorylation of the receptor

Initial receptor desensitisation may occur without receptor internalisation.
Internalisation is the process where cell surface receptors are moved from the plasma membrane to the inside of the cell. Cytoskeletal elements are important for both internalisation and reinsertion of receptors into the cellular membrane.

Acute desensitisation results in a rapid decrease in the response with the return of the response occurring without new receptor synthesis. However, long term desensitisation results in decrease in receptor expression over time that requires synthesis to replace receptors.

This indicates that decrease in muscarinic receptors occurs in two phases:
- Internalisation, in which the receptors can still be bound to the G protein and can be reinserted into the membrane
- This is followed by downregulation.

Question 9

Briefly discuss the densitisation of the nicotinic Ach receptor in the motor endplate.

Answer 9

The depolarisation induced by Ach at the NMJ membrane of the muscle fibre reaches a maximum and gradually falls despite the consistent concentration of the agonist.
Desensitisation in respect of the post-junctional membrane manifests as a progressive decline in the induced conductance during prolonged contact with Ach or other cholinomimetics.