Gpr3 Stimulates Aβ Production Via Interactions with APP and β-arrestin2

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Sep 27

PMID 24069330

Citations 21

Authors

Christopher D Nelson

Morgan Sheng

Affiliations

Soon will be listed here.

Abstract

The orphan G protein-coupled receptor (GPCR) GPR3 enhances the processing of Amyloid Precursor Protein (APP) to the neurotoxic beta-amyloid (Aβ) peptide via incompletely understood mechanisms. Through overexpression and shRNA knockdown experiments in HEK293 cells, we show that β-arrestin2 (βarr2), a GPCR-interacting scaffold protein reported to bind γ-secretase, is an essential factor for GPR3-stimulated Aβ production. For a panel of GPR3 receptor mutants, the degree of stimulation of Aβ production correlates with receptor-β-arrestin binding and receptor trafficking to endocytic vesicles. However, GPR3's recruitment of βarr2 cannot be the sole explanation, because interaction with βarr2 is common to most GPCRs, whereas GPR3 is relatively unique among GPCRs in enhancing Aβ production. In addition to β-arrestin, APP is present in a complex with GPR3 and stimulation of Aβ production by GPR3 mutants correlates with their level of APP binding. Importantly, among a broader selection of GPCRs, only GPR3 and prostaglandin E receptor 2 subtype EP2 (PTGER2; another GPCR that increases Aβ production) interact with APP, and PTGER2 does so in an agonist-stimulated manner. These data indicate that a subset of GPCRs, including GPR3 and PTGER2, can associate with APP when internalized via βarr2, and thereby promote the cleavage of APP to generate Aβ.

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References

Benovic J, Kuhn H, Weyand I, CODINA J, Caron M, Lefkowitz R . Functional desensitization of the isolated beta-adrenergic receptor by the beta-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Acad Sci U S A. 1987; 84(24):8879-82. PMC: 299654. DOI: 10.1073/pnas.84.24.8879. View

Acharya S, Karnik S . Modulation of GDP release from transducin by the conserved Glu134-Arg135 sequence in rhodopsin. J Biol Chem. 1996; 271(41):25406-11. DOI: 10.1074/jbc.271.41.25406. View

. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 2012; 8(2):131-68. DOI: 10.1016/j.jalz.2012.02.001. View

Qiu C, Kivipelto M, von Strauss E . Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009; 11(2):111-28. PMC: 3181909. View

Selkoe D . Resolving controversies on the path to Alzheimer's therapeutics. Nat Med. 2011; 17(9):1060-5. DOI: 10.1038/nm.2460. View

Lefkowitz R, Inglese J, Koch W, Pitcher J, Attramadal H, Caron M . G-protein-coupled receptors: regulatory role of receptor kinases and arrestin proteins. Cold Spring Harb Symp Quant Biol. 1992; 57:127-33. DOI: 10.1101/sqb.1992.057.01.016. View

Freedman N, Lefkowitz R . Desensitization of G protein-coupled receptors. Recent Prog Horm Res. 1996; 51:319-51; discussion 352-3. View

Seeburg D, Sheng M . Activity-induced Polo-like kinase 2 is required for homeostatic plasticity of hippocampal neurons during epileptiform activity. J Neurosci. 2008; 28(26):6583-91. PMC: 3844828. DOI: 10.1523/JNEUROSCI.1853-08.2008. View

Mehlmann L, Saeki Y, Tanaka S, Brennan T, Evsikov A, Pendola F . The Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes. Science. 2004; 306(5703):1947-50. DOI: 10.1126/science.1103974. View

10.

Ahn S, Nelson C, Garrison T, Miller W, Lefkowitz R . Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference. Proc Natl Acad Sci U S A. 2003; 100(4):1740-4. PMC: 149903. DOI: 10.1073/pnas.262789099. View

11.

DeWire S, Ahn S, Lefkowitz R, Shenoy S . Beta-arrestins and cell signaling. Annu Rev Physiol. 2007; 69:483-510. DOI: 10.1146/annurev.physiol.69.022405.154749. View

12.

Ni Y, Zhao X, Bao G, Zou L, Teng L, Wang Z . Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. Nat Med. 2006; 12(12):1390-6. DOI: 10.1038/nm1485. View

13.

Lefkowitz R, Whalen E . beta-arrestins: traffic cops of cell signaling. Curr Opin Cell Biol. 2004; 16(2):162-8. DOI: 10.1016/j.ceb.2004.01.001. View

14.

Luttrell L, Ferguson S, Daaka Y, Miller W, Maudsley S, Della Rocca G . Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science. 1999; 283(5402):655-61. DOI: 10.1126/science.283.5402.655. View

15.

Guan X, Kobilka T, Kobilka B . Enhancement of membrane insertion and function in a type IIIb membrane protein following introduction of a cleavable signal peptide. J Biol Chem. 1992; 267(31):21995-8. View

16.

Thathiah A, Horre K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M . β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat Med. 2012; 19(1):43-9. DOI: 10.1038/nm.3023. View

17.

Shenoy S, Lefkowitz R . Trafficking patterns of beta-arrestin and G protein-coupled receptors determined by the kinetics of beta-arrestin deubiquitination. J Biol Chem. 2003; 278(16):14498-506. DOI: 10.1074/jbc.M209626200. View

18.

Greasley P, Fanelli F, Scheer A, Abuin L, Debenedetti P, Cotecchia S . Mutational and computational analysis of the alpha(1b)-adrenergic receptor. Involvement of basic and hydrophobic residues in receptor activation and G protein coupling. J Biol Chem. 2001; 276(49):46485-94. DOI: 10.1074/jbc.M105791200. View

19.

Jonsson T, Atwal J, Steinberg S, Snaedal J, Jonsson P, Bjornsson S . A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012; 488(7409):96-9. DOI: 10.1038/nature11283. View

20.

Laporte S, Oakley R, Zhang J, Holt J, Ferguson S, Caron M . The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci U S A. 1999; 96(7):3712-7. PMC: 22359. DOI: 10.1073/pnas.96.7.3712. View