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Retromer arrests receptor on the run

Parathyroid hormone analogue PTH(1–34), used clinically to treat osteoporosis, forms a stable complex with its receptor and prolongs cAMP production even after internalization and recruitment to endosomes. New data suggests this signaling cascade is stimulated by β -arrestins and terminated by retromer. The parathyroid hormone receptor (PTHR) is a G protein-coupled receptor (GPCR) present in bone and kidney cells that regulates calcium levels in the blood and homeostasis between bone resorption and growth. A synthetic analogue of the parathyroid hormone, PTH(1–34), is clinically used to stimulate bone formation in some patients suffering from osteoporosis. Treatment is dependent on the dosage of PTH(1–34) as intermittent administration results in bone growth, continuous administration stimulates bone resorption. PTH(1–34) forms an unusually stable complex with the PTHR, resulting in prolonged activation of the receptor and elevated levels of the second messenger cAMP, even after internalization of the PTHR-PTH(1–34) complex. Feinstein and colleagues now address how signaling of this receptor-ligand complex is terminated, given that removal from the plasma membrane does not seem to suffice 1 . Canonical GPCR signaling is silenced by β -arrestins (Fig 1A), however the authors find that β –arrestins actually prolong PTHR-PTH(1–34) signaling, and that this signal is terminated by retromer. Using FRET to monitor the level of cAMP in live cells, Feinstein et al . provide evidence that β -arrestins actually enhance cAMP signaling by PTHR-PTH(1–34). Time-lapse co-localization studies show that β -arrestin1 is recruited to the plasma membrane upon PTH(1– 34) stimulation and remains co-localized with the PTHR after internalization, forming a dynamic complex on endosomes as indicated by FRAP experiments. Twenty-five minutes after stimulation, the co-localization of the receptor and β -arrestin1 drops, which coincides with an increase of PTHR co-localization and interaction with the retromer complex. Co-localization of retromer with PTHR is decreased or delayed by co-expression of mutant β -arrestin1[VI-AA] with increased affinity for the PTHR, suggesting that β -arrestin1 and retromer compete for PTHR binding. It is argued that retromer association with the active PTHR negatively regulates its cAMP signal: overexpression of retromer components attenuate the cAMP level upon PTH(1–34) stimulation and depletion of the retromer component VPS35 prolongs the cAMP signal. The retromer-mediated attenuation of cAMP