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GPCR heteromers: An overview of their classification, function and physiological relevance
Natasha C Dale1,2, Elizabeth K M Johnstone1,2,3, Kevin D G Pfleger1,2,4
1Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia.
Frontiers in Endocrinology
|September 16, 2022
Summary
G protein-coupled receptors (GPCRs) form complexes called heteromers, altering their function and offering new therapeutic targets. Understanding GPCR heteromer pharmacology is key to developing effective drugs with fewer side effects.
Area of Science:
- Pharmacology
- Molecular Biology
- Drug Discovery
Background:
- G protein-coupled receptors (GPCRs) can form higher-order structures like homomers and heteromers.
- GPCR heteromerization significantly impacts receptor expression, ligand binding, signaling, and trafficking.
- GPCR heteromers are emerging as promising drug targets due to their unique pharmacological properties.
Purpose of the Study:
- To explore the functional implications of GPCR heteromerization.
- To highlight the therapeutic potential of targeting GPCR heteromers.
- To underscore the need for improved understanding of GPCR heteromer pharmacology and physiology.
Main Methods:
- Literature review on GPCR heteromerization.
- Analysis of reported changes in receptor pharmacology and trafficking upon heteromerization.
- Examination of current strategies for targeting GPCR heteromers.
Main Results:
- GPCR heteromerization leads to altered ligand affinity, efficacy, and G protein coupling.
- Changes in internalization, trafficking kinetics, and β-arrestin interactions are associated with heteromer formation.
- Bivalent ligands are currently the primary approach for targeting GPCR heteromers due to challenges in developing specific ligands.
Conclusions:
- GPCR heteromers exhibit distinct pharmacological profiles compared to their monomeric counterparts.
- Further research into GPCR heteromer function is crucial for advancing drug development.
- Developing heteromer-specific ligands could lead to more efficacious therapeutics with reduced adverse effects.
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