LRP6 mediates cAMP generation by G protein-coupled receptors through regulating the membrane targeting of Gαs

Mei Wan, Jun Li, Katie Herbst, Jin Zhang, Bing Yu, Xiangwei Wu, Tao Qiu, Weiqi Lei, Charlotta Lindvall, Bart O. Williams, Hairong Ma, Fengjie Zhang, Xu Cao

Research output: Contribution to journalArticlepeer-review

Abstract

Ligand binding to certain heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) stimulates the rapid synthesis of cyclic adenosine monophosphate (cAMP) through the G protein αs subunit, which activates adenylyl cyclase (AC). We found that the transmembrane receptor low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor for Wnt proteins, bound to the Gαsβγ heterotrimer and that knockdown of LRP6 attenuated cAMP production by various GPCRs, including parathyroid hormone receptor 1 (PTH1R). Knockdown of LRP6 disrupted the localization of Gαs to the plasma membrane, which led to a decrease in the extent of coupling of Gαs to PTH1R and inhibited the production of cAMP and the activation of cAMP-dependent protein kinase (PKA) in response to PTH. PKA phosphorylated LRP6, which enhanced the binding of Gαs to LRP6, its localization to the plasma membrane, and the production of cAMP in response to PTH. Decreased PTH-dependent cAMP production was observed in single cells in which LRP6 was knocked down or mutated at the PKA site by monitoring the cAMP kinetics. Thus, we suggest that the binding of Gαs to LRP6 is required to establish a functional GPCR-Gαs-AC signaling pathway for the production of cAMP, providing an additional regulatory component to the current GPCR-cAMP paradigm.

Original languageEnglish (US)
Article numberra15
JournalScience signaling
Volume4
Issue number164
DOIs
StatePublished - Mar 15 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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