Tools & Resources / Document Resource Library / Documents / Multi-Parameter GPCR Screening: An Essential Tool for Uncovering GPCR Mutant Phenotypes

Multi-Parameter GPCR Screening: An Essential Tool for Uncovering GPCR Mutant Phenotypes

Multi-Parameter GPCR Screening: An Essential Tool for Uncovering GPCR Mutant Phenotypes
Version:
V1

File Name/Number:
2013 SLAS

Year:
2013

Download as PDF
The recent appreciation of functional selectivity/ligand bias in GPCR signaling has uncovered new opportunities for therapeutic discovery and continues to increase our understanding of compound function. We reasoned that since ligands and hence receptor conformation can differentially stimulate particular signaling pathways, variations in amino acid composition could similarly bias receptors and their responses to ligand. To test this hypothesis, we have compared a number of common GPCR variants and their wild-type counterparts in their ability to traffic to the cell surface and signal through g-proteins, arrestin, and internalization. This comprehensive suite of assays appropriately described mutants that caused GPCR misfolding and ER retention, as well as detailed changes in the functional selectivity of compounds. Thus the combination of these platforms provides an unprecedented view of GPCR variant activity in a quantifiable and comparable manner amenable to paneling large numbers of variants. These tools can be used identify new prospects for existing compounds and stratify patient populations for similar responses to drug candidates.