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

Alex D. White, Frederic G. Jean-Alphonse, Fei Fang, Karina A. Peña, Shi Liu, Gabriele M. König, Asuka Inoue, Despoina Aslanoglou, Samuel H. Gellman, Evi Kostenis, Kunhong Xiao, Jean Pierre Vilardaga

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

cAMP production upon 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 endosomal cAMP responses. Inhibition of Gq/11 signaling by FR900359 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 Gβγ subunits, which, in turn, act in a phosphoinositide-3 kinase-dependent manner to promote the assembly of PTHR- βarrestin-Gβγ signaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal regulation of Gs-dependent cAMP signaling.

Original languageEnglish
Pages (from-to)7455-7460
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number13
DOIs
Publication statusPublished - 2020 Mar 31

Keywords

  • CAMP
  • Endosomal signaling
  • G-proteins
  • GPCR
  • PTH

ASJC Scopus subject areas

  • General

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