NIH Research Festival
G protein coupled receptors (GPCRs) are the target of about 35% of FDA-approved drugs, which underlines their importance in pharmacological interventions. Agonist binding to GPCRs activates heterotrimeric G-proteins and Œ≤-arrestins to initiate downstream signaling, followed by receptor desensitization and endocytosis. Œ≤-arrestins terminate G-protein signaling and promote GPCR internalization thereby reducing the number of receptors in the plasma membrane (PM). and causing loss of responsiveness to agonists. Based on the current view, GPCRs must reach the endolysosomal system to uncouple from their arrestin partner followed by dephosphorylation to regain their resting state, thus becoming capable to fulfil their function in the recurring signaling cycle.
Phosphatidylinositol 4,5-bisphosphate (PIP2) is known to affect several proteins that play key roles in endocytosis, but their role in GPCR desensitization is unknown. We found that knock down (KD) of either EFR3A or PIP5K1A (but not B or C), key players in PIP2 synthesis promoted receptor desensitization without changing the overall PIP2 levels in the PM. We also identified that silencing AP2, but not clathrin heavy chain, dynamin 1 or -2, accelerated AT1R desensitization, while all these manipulations inhibited receptor endocytosis. As expected, Œ≤-arrestin2 KD prevented receptor desensitization, but unexpectedly, KD of Œ≤arr1 promoted desensitization of AT1Rs. None of the manipulations affected signaling of the truncated desensitization deficient AT1R confirming that these effects were specific for receptor desensitization. These results suggest, that contrary to current believes, re-sensitization of GPCRs can occur without their endocytosis and likely occurs at the PM at specific steps during clathrin-coated pit maturation.
Scientific Focus Area: Molecular Pharmacology
This page was last updated on Monday, September 25, 2023