Fast-diffusing receptor collisions with slow-diffusing peptide ligand assemble the ternary parathyroid hormone-GPCR-arrestin complex.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39627206.
- Also identified by DOI 10.1038/s41467-024-54772-3 and PMC identifier 11615292.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The assembly of a peptide ligand, its receptor, and β-arrestin (βarr) into a ternary complex within the cell membrane is a crucial aspect of G protein-coupled receptor (GPCR) signaling. We explore this assembly by attaching fluorescent moieties to the parathyroid hormone (PTH) type 1 receptor (PTH<sub>1</sub>R), using PTH as a prototypical peptide hormone, along with βarr and clathrin, and recording dual-color single-molecule imaging at the plasma membrane of live cells. Here we show that PTH<sub>1</sub>R exhibits a near-Brownian diffusion, whereas unbound hormone displays limited mobility and slow lateral diffusion at the cell surface. The formation of the PTH-PTH<sub>1</sub>R-βarr complex occurs in three sequential steps: (1) receptor and ligand collisions, (2) phosphoinositide (PIP<sub>3</sub>)-dependent recruitment and conformational change of βarr molecules at the plasma membrane, and (3) collision of most βarr molecules with the ligand-bound receptor within clathrin clusters. Our results elucidate the non-random pathway by which PTH-PTH<sub>1</sub>R-βarr complex is formed and unveil the critical role of PIP<sub>3</sub> in regulating GPCR signaling.
Medical subject headings
- Receptor, Parathyroid Hormone, Type 1
- Parathyroid Hormone
- Cell Membrane
- beta-Arrestins
- Signal Transduction