Rewiring PTH receptor signaling: Hormone dimerization restores endosomal signaling lost in hypocalcemia-linked PTH mutant.

ABSTRACT: G protein-coupled receptors often form dimers and heterodimers at the plasma membrane to transduce signals from various ligands, including peptide hormones. However, the role of homodimerization in regulating signaling by the parathyroid hormone (PTH) type 1 receptor (PTH₁R) has remained ambiguous. Here, we show that PTH₁R exists as a monomer in live cells under both basal and ligand-bound conditions, even in the presence of a dimeric form of the PTH mutant, PTH^R25C (residue 25 of PTH), which is linked with hypoparathyroidism. Single-molecule fluorescence imaging and single-cell FRET assays support the monomeric behavior of PTH₁R, with molecular dynamics simulations using weighted ensemble sampling revealing that PTH^R25C destabilizes t

SUBMITTER: Pacheco J 

PROVIDER: S-EPMC12718132 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature