Signaling: retromer arrests receptor on the run

Abstract

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.

Figure 1. Canonical and non-canonical GPCR-cAMP signaling.

A) The classic model of GPCR signaling starts with the binding of ligand to the receptor, which induces the exchange of GDP for GTP on Gα subunit of heterotrimeric G proteins on the inner leaflet of the plasma membrane. Active GTP-Gα subsequently stimulates adenylyl cyclase to produce second messenger cAMP. cAMP in its turn activates protein kinase A, which has many downstream targets to affect the cell’s behaviour. The second messenger signal is terminated by the association of β-arrestins to the receptor-ligand complex, competing with Gα binding. β-arrestins associate with clathrin to trigger internalization of the receptor-ligand complex, which removes the active receptor from the plasma membrane. B) The PTHR-PTH(1–34) complex is unusually stable and continues to produce cAMP after β-arrestin binding and internalization in the presence of G-protein and adenylyl cyclase. The cAMP signal is terminated by exchange of β-arrestin for retromer, upon which the silenced PTHR is transported to the TGN.