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G q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR
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Edité par CCSD ; National Academy of Sciences -
International audience. cAMP production upon activation of Gsby G protein-coupled receptors has classically been considered to be plasma membrane-delimited, but a shift in this paradigm has occurred in recent years with the identification of several receptors that continue to signal from early endosomes after internalization. The molecular mech-anisms regulating this aspect of signaling remain incompletely understood. Here, we investigated the role of Gq/11 activation by the parathyroid hormone (PTH) type 1 receptor (PTHR) in mediating endosomal cAMP responses. Inhibition of Gq/11signaling by FR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gαq/11. We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cellsurface Gβγ subunits, which, in turn, act in a phosphoinositide-3kinase-dependent manner to promote the assembly of PTHR–βarrestin–Gβγsignaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal reg-ulation of Gs-dependent cAMP signaling
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