3.3 Flashcards
(35 cards)
What percentage of current drugs target GPCRs?
Around 30%.
Why are GPCRs major drug targets?
They regulate diverse physiological functions and are accessible on the cell surface.
What were traditional assumptions about GPCRs?
Single G protein coupling, uniform signalling by all agonists, monomeric structure, signalling ceases upon internalisation.
What are the updated views of GPCR behaviour?
Multiple effectors, biased signalling, allosteric modulation, oligomerisation, and compartmentalised signalling.
What is biased signalling?
Differential activation of downstream effectors due to specific receptor conformations stabilised by ligands, receptors, or system components.
What are the three types of signalling bias?
Ligand bias, receptor bias, and system bias.
What is ligand bias?
A ligand stabilises a unique conformation that favours certain signalling pathways.
What is receptor bias?
Receptor modifications (e.g. mutations, PTMs) alter ligand or effector interaction.
What is system bias?
Cellular context (e.g. effector expression) affects which pathways dominate.
Give an example of a drug with ligand bias.
Oliceridine – a biased μ-opioid receptor agonist.
What is GPCR allosterism?
Modulation of receptor activity by ligands binding outside the orthosteric site.
What are the types of allosteric modulators (AMs)?
PAMs (positive), NAMs (negative), and neutral AMs.
Do AMs have intrinsic efficacy?
No – they require orthosteric ligand presence to exert effects.
What are 4 key advantages of allosteric modulation?
1) Preserves natural signalling rhythms, 2) Effect saturation (limits overdosing), 3) Greater subtype selectivity, 4) Enables targeting ‘undruggable’ GPCRs.
What is an example of successful AM development?
Maraviroc – blocks HIV-1 entry by decreasing CCR5 binding to gp120.
What is GPCR oligomerisation?
Formation of GPCR dimers or trimers (homo- or hetero-).
What are obligate vs non-obligate oligomers?
Obligate: required for function; Non-obligate: functional as monomers but can dimerise.
What was the first known GPCR obligate heteromer?
GABAB1-GABAB2 (1998).
What is the role of GABAB1 and GABAB2?
GABAB1: ligand binding; GABAB2: G protein activation and trafficking.
How does μ-OR homodimerisation affect morphine tolerance?
DAMGO-induced internalisation enables resensitisation of morphine-bound receptors.
How can mutant GPCRs affect wild-type GPCRs?
Via dominant-negative effects (e.g., CCR5Δ32 reduces surface expression of CCR5 and delays HIV progression).
What is heteromerisation?
Complex formation between different GPCRs, leading to new properties.
What aspects of GPCR function can be altered by heteromerisation?
Surface expression, internalisation, ligand binding, signalling pathways, desensitisation.
What is a clinical example of GPCR heteromer relevance?
AT1–CCR2 heteromer in chronic kidney disease (CKD).
