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Background  A sensitive balance between receptor activation and desensitization is crucial for cellular homeostasis. Like many other GPCR, the human neuropeptide Y 2  receptor (hY 2 R) undergoes ligand dependent activation and internalization into intracellular compartments, followed by recycling to the plasma membrane. This receptor is involved in the pathophysiology of distinct diseases e.g. epilepsy and cancer progression and conveys anorexigenic signals which makes it an interesting and promising anti-obesity target. However, Y 2 R desensitization was observed after daily treatment with a selective PYY 13–36  analog in vivo by a yet unknown mechanism.    Materials  We studied the desensitization and activatability of recycled Y 2 R in transiently transfected HEK293 cells as well as in endogenously Y 2 R expressing SH-SY5Y and SMS-KAN cells. Results were evaluated by one-way ANOVA and Tukey post test.    Results  We observed strong desensitization of the Y 2 R in a second round of stimulation despite its reappearance at the membrane. Already the first activation of the Y 2 R leads to depletion of the functional cellular Gα i/o  protein pool and consequently desensitizes the linked signal transduction pathways, independent of receptor internalization. This desensitization also extends to other Gα i/o -coupled GPCR and can be detected in transfected HEK293 as well as in SH-SY5Y and SMS-KAN cell lines, both expressing the Y 2 R endogenously. By overexpression of chimeric Gα qi  proteins in a model system, activation has been rescued, which identifies a critical role of the G protein status for cellular signaling. Furthermore, Y 2 R displays strong allosteric coupling to inhibitory G proteins in radioligand binding assays, and loses 10-fold affinity in the G protein-depleted state observed after activation, which can be largely abrogated by overexpression of the Gα i -subunit.    Conclusion  The unusually persistent Gα i -signaling of the Y 2 R leads to a state of cellular desensitization of the inhibitory Gα i -pathway. The strong allosteric effects of the Y 2 R-Gα i -interaction might be a mechanism that contributes to the burst of Gα i -signaling, but also serves as a mechanism to limit the Y 2 -mediated signaling after recycling. Thus, the cell is left in a refractory state, preventing further Gα i -signaling of the Y 2 R itself but also other Gα i/o -coupled receptors by simply controlling the repertoire of downstream effectors.Video abstractGraphical abstract

Unusually persistent Gαi-signaling of the neuropeptide Y2 receptor depletes cellular Gi/o pools and leads to a Gi-refractory state