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Sci. Signal., 15 March 2011
Vol. 4, Issue 164, p. ra15
[DOI: 10.1126/scisignal.2001464]

RESEARCH ARTICLES

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

Mei Wan1*, Jun Li1,2, Katie Herbst3, Jin Zhang3, Bing Yu1, Xiangwei Wu1,2, Tao Qiu1, Weiqi Lei1, Charlotta Lindvall4, Bart O. Williams4, Hairong Ma1, Fengjie Zhang1,2, and Xu Cao1*

1 Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 Shihezi Medical College, Shihezi University, Xinjiang 832002, China.
3 Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4 Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI 49503–2518, USA.

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 Gαsβ{gamma} 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.

* To whom correspondence should be addressed. E-mail: mwan4{at}jhmi.edu (M.W.); xcao11{at}jhmi.edu (X.C.)

Citation: M. Wan, J. Li, K. Herbst, J. Zhang, B. Yu, X. Wu, T. Qiu, W. Lei, C. Lindvall, B. O. Williams, H. Ma, F. Zhang, X. Cao, LRP6 Mediates cAMP Generation by G Protein–Coupled Receptors Through Regulating the Membrane Targeting of Gαs. Sci. Signal. 4, ra15 (2011).

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