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G q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

ABSTRACT: cAMP production on activation of Gs by G protein-coupled receptors has classically been considered to be plasma membranedelimited, 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 mechanisms 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 endosomalcAMPresponses.InhibitionofGq/11 signalingbyFR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gaq/11. We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cell surface Gbr subunits, which, in turn, act in a phosphoinositide3 kinase dependent manner to promote the assembly of PTHR barrestinGbr signaling complexes that mediate endosomal cAMP responses. These resultsunveil insights intothe spatiotemporalregulation of Gs-dependent cAMP signaling.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Kunhong Xiao

PROVIDER: MSV000085051 | MassIVE | Tue Mar 03 09:29:00 GMT 2020

REPOSITORIES: MassIVE

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