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

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 α_s 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 Gα_sβγ 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 Gα_s to the plasma membrane, which led to a decrease in the extent of coupling of Gα_s 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 Gα_s 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 Gα_s to LRP6 is required to establish a functional GPCR-Gα_s-AC signaling pathway for the production of cAMP, providing an additional regulatory component to the current GPCR-cAMP paradigm.