Unusually persistent Gα i -signaling of the neuropeptide Y 2 receptor depletes cellular G i/o pools and leads to a G i -refractory state

摘要: A sensitive balance between receptor activation and desensitization is crucial for cellular homeostasis. Like many other GPCR, the human neuropeptide Y2 (hY2R) undergoes ligand dependent internalization into intracellular compartments, followed by recycling to plasma membrane. This involved in pathophysiology of distinct diseases e.g. epilepsy cancer progression conveys anorexigenic signals which makes it an interesting promising anti-obesity target. However, Y2R was observed after daily treatment with a selective PYY13–36 analog vivo yet unknown mechanism. We studied activatability recycled transiently transfected HEK293 cells as well endogenously expressing SH-SY5Y SMS-KAN cells. Results were evaluated one-way ANOVA Tukey post test. strong second round stimulation despite its reappearance at Already first leads depletion functional Gαi/o protein pool consequently desensitizes linked signal transduction pathways, independent internalization. also extends Gαi/o-coupled GPCR can be detected cell lines, both endogenously. By overexpression chimeric Gαqi proteins model system, has been rescued, identifies critical role G status signaling. Furthermore, displays allosteric coupling inhibitory radioligand binding assays, loses 10-fold affinity protein-depleted state activation, largely abrogated Gαi-subunit. The unusually persistent Gαi-signaling Gαi-pathway. effects Y2R-Gαi-interaction might mechanism that contributes burst Gαi-signaling, but serves limit Y2-mediated signaling recycling. Thus, left refractory state, preventing further itself receptors simply controlling repertoire downstream effectors.