The Molecular Process of GPCR Desensitisation

G-Protein Coupled Receptors (GPCRs)

• GPCRs are critical for numerous biological functions and are targets for over 30% of prescribed drugs.
  • Examples of GPCR drugs:
  • Salbutamol: β2 adrenoceptor agonist used for asthma.
  • Morphine: μ/κ opiate receptor agonist used for pain relief.
  • Losartan: AT1 receptor antagonist used for hypertension.

Mechanisms of GPCR Signalling Regulation

• GPCR signalling can be regulated through:
  • Receptor-mediated methods by processes such as desensitisation.
  • Non-receptor mediated methods involving the removal of agonists and degradation of second messengers.

Desensitisation Processes

• Homologous Desensitisation:

  • Affects a single receptor type through specific mechanisms linked to that receptor.
  • Involves phosphorylation of receptor by GPCR kinases (GRKs) leading to arrestin recruitment.

• Heterologous Desensitisation:

  • Involves the activation of one receptor leading to desensitisation of another receptor type.
  • Often linked to second messenger production (e.g., cAMP).

Role of Arrestin in Homologous Desensitisation

• Arrestin acts as a scaffold protein in the desensitisation process:
  • Binding of Arrestin:
  • After GRK phosphorylates the receptor, arrestin binds to it, preventing further G-protein interaction.
  • Recruits phosphodiesterases to lower cAMP levels, contributing to desensitisation.

Mechanisms of Non-Receptor Regulation

• Non-receptor methods to regulate GPCR signalling include:
  • Removal of Agonist: Through enzymatic degradation (e.g., acetylcholinesterase degrading ACh).
  • Sequestration of Agonist: Transport of neurotransmitters (e.g., dopamine, serotonin) back from the synapse to the neurons.
  • Rapid Degradation of Second Messengers: Enzymes like phosphodiesterases break down cAMP and cGMP.

Time Courses of GPCR Desensitisation

• Phases of Desensitisation:
  • Rapid phase: Due to receptor phosphorylation, occurs within minutes.
  • Slow phase: Due to receptor down-regulation, takes hours for recovery.
• Recovery Mechanisms:
  • Receptors may be recycled back to the membrane or be degraded in lysosomes after ubiquitination.

Biased Ligands and Opioid Receptor Signalling

• Biased GPCR ligands offer a potential way to increase selectivity and reduce side effects:
  • These ligands can preferentially activate G-protein signalling or arrestin-mediated pathways.
  • Mu-Opioid Receptor (MOR) Biased Agonists: Such as TRV130, developed to provide analgesia with reduced risk of respiratory depression.

Summary of Key Points

1. Mechanisms of Regulation:
   • Desensitisation of GPCRs can be homologous or heterologous.
2. Role of GRKs and Arrestin:
   • GRKs phosphorylate receptors; arrestin mediates desensitisation and desensitisation-induced internalisation.
3. Arrestin-Dependent Signalling:
   • In addition to desensitisation, arrestin can participate in independent signalling pathways, contributing to the development of biased agonists.
4. Current Research and Clinical Relevance:
   • Exploring agonists that promote selective analgesia without side effects (e.g., respiratory suppression).

Further Reading

• Explore literature from: Walther & Ferguson (2013), Rajagopal & Shenoy (2018), and others for deeper insights into GPCR signalling and biased agonism.