Biased agonists at the human Y 1 receptor lead to prolonged membrane residency and extended receptor G protein interaction

Biased agonists at the human Y 1 receptor lead to prolonged membrane residency and extended receptor G protein interaction:

Abstract

Functionally selective ligands to address specific cellular responses downstream of G protein-coupled receptors (GPCR) open up new possibilities for therapeutics. We designed and characterized novel subtype- and pathway-selective ligands. Substitution of position Q³⁴ of neuropeptide Y to glycine (G³⁴-NPY) results in unprecedented selectivity over all other YR subtypes. Moreover, this ligand displays a significant bias towards activation of the G_i/o pathway over recruitment of arrestin-3. Notably, no bias is observed for an established Y₁R versus Y₂R selective ligand carrying a proline at position 34 (F⁷,P³⁴-NPY). Next, we investigated the spatio-temporal signaling at the Y₁R and demonstrated that G protein-biased ligands promote a prolonged localization at the cell membrane, which leads to enhanced G protein signaling, while endosomal receptors do not contribute to cAMP signaling. Thus, spatial components are critical for the signaling of the Y₁R that can be modulated by tailored ligands and represent a novel mode for biased pathways.

Graphic abstract