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Retromer terminates the generation of cAMP by internalized G protein‐coupled PTH receptors

Generation of cyclic AMP by GPCRs and its termination is currently thought to occur exclusively at the plasma membrane of cells. Under existing models of receptor regulation, this signal is primarily restricted by desensitization of the receptors through their binding to β‐arrestins. However, this paradigm cannot explain recent observations that the PTHR continues to stimulate cAMP production in cultured cells and in vivo even after receptor internalization, as β‐arrestins are known to rapidly bind and internalize activated PTHR. Here we show both in kidney and bone cultured cells that β‐arrestin1 binding prolongs rather than terminates cAMP generation by PTHR, and that cAMP generation correlates with the persistence of arrestin‐receptor complexes on endosomes. Modulating the duration of cAMP signaling using either modified PTH analogs or mutant arrestin caused corresponding changes in the duration of PTHR‐arrestin co‐localization. We found that PTHR signaling is instead turned‐off by the retromer complex, which regulates traffic of internalized receptor from endosomes to the Golgi apparatus. Termination of cAMP generation coincides with the transfer of PTHR from an arrestin‐ to a retromer‐labeled domain on individual endosomes. Thus, binding by the retromer complex regulates sustained cAMP generation triggered by an internalized GPCR.