Research ArticleCell Biology

LRP6 Mediates cAMP Generation by G Protein–Coupled Receptors Through Regulating the Membrane Targeting of Gαs

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Science Signaling  15 Mar 2011:
Vol. 4, Issue 164, pp. ra15
DOI: 10.1126/scisignal.2001464

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Unexpected Partner

Signaling by heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) that respond to hormones, such as parathyroid hormone receptor 1 (PTH1R), has been extensively characterized. Ligand binding to the certain classes of GPCRs results in the activation of G proteins that contain the Gαs subunit, which stimulates the effector adenylyl cyclase (AC) to generate the second messenger (cAMP). Wan et al. have shown that low-density lipoprotein receptor–related protein 6 (LRP6), a transmembrane co-receptor for Wnt proteins, was required for efficient activation of Gαs-mediated cAMP signaling by various GPCRs, including PTH1R, through a mechanism that involved LRP6-mediated recruitment of Gαs-containing G proteins to receptors at the plasma membrane. PKA, a kinase activated by cAMP, phosphorylated LRP6, which enhanced its binding to Gαs. AC is the therapeutic target in the treatment of various hormonal disorders; the data of Wan et al. suggest that modulation of LRP6 activity may provide an additional strategy.

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