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Orphan receptor GPR37L1 remains unliganded

Nature Chemical Biology volume 17, pages 383–386 (2021)Cite this article

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The Original Article was published on 19 December 2016

arising from T. Ngo et. al. Nature Chemical Biology https://doi.org/10.1038/nchembio.2266 (2017)

Orphan G-protein-coupled receptors (GPCRs) are largely intractable therapeutic targets, owing to the lack of chemical tools for exploring their pharmacology. The discovery of such tools, however, is hampered by a number of unknowns, such as effector coupling and appropriate positive controls. In our 2017 Nature Chemical Biology paper1, we developed a computational chemical tool discovery approach called GPCR Contact-Informed Neighboring Pocket (GPCR-CoINPocket). This method predicted pharmacological similarity of GPCRs in a ligand- and structure-independent manner, to enable the discovery of off-target activities of known compounds at orphan GPCRs and hence the identification of so-called surrogate ligands. Our orphan GPCR target for prospective surrogate ligand discovery efforts was GPR37L1, a brain-specific receptor linked to cerebellar development2 and seizures3. We had previously demonstrated that GPR37L1 constitutively coupled to Gαs and generated ligand-independent increases in intracellular cyclic AMP (cAMP)4. Thus, the inverse agonist activities of computationally predicted surrogates were tested in a cAMP-response element (CRE)–luciferase reporter gene assay in human embryonic kidney (HEK293) cells expressing either vector control or what we thought was untagged GPR37L1 in pcDNA3.1. However, we recently discovered that the GPR37L1 construct used in both studies was incorrect: instead of pcDNA3.1, the receptor was inserted backwards into a yeast p426GPD vector (hereafter referred to as p426-r37L1). We reported the issue to the editors of Science Signaling and Nature Chemical Biology, which eventually led to the retraction of both papers1,4. Here we correct the cloning error and describe our subsequent unsuccessful efforts to retest the computationally predicted GPR37L1 ligands.

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Fig. 1: The corrected GPR37L1 construct does not have the apparent Gαs constitutive activity seen with p426-r37L1.
Fig. 2: The corrected GPR37L1 construct does not display constitutive or ligand-induced activity in any assays examined.

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Source data are provided with this paper.

References

  1. Ngo, T. et al. Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat. Chem. Biol. 13, 235–242 (2017); retraction https://doi.org/10.1038/s41589-021-00746-1 (2021).

  2. Marazziti, D. et al. Precocious cerebellum development and improved motor functions in mice lacking the astrocyte cilium-, patched 1-associated Gpr37l1 receptor. Proc. Natl Acad. Sci. USA 110, 16486–16491 (2013).

    Article  CAS  Google Scholar 

  3. Giddens, M. M. et al. GPR37L1 modulates seizure susceptibility: evidence from mouse studies and analyses of a human GPR37L1 variant. Neurobiol. Dis. 106, 181–190 (2017).

    Article  CAS  Google Scholar 

  4. Coleman, J. L. et al. Metalloprotease cleavage of the N terminus of the orphan G protein-coupled receptor GPR37L1 reduces its constitutive activity. Sci. Signal. 9, ra36 (2016); retraction 612, eaba2063 (2019).

  5. Jiang, L. I. et al. Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway. J. Biol. Chem. 282, 10576–10584 (2007).

    Article  CAS  Google Scholar 

  6. Meyer, R. C., Giddens, M. M., Schaefer, S. A. & Hall, R. A. GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin. Proc. Natl Acad. Sci. USA 110, 9529–9534 (2013).

    Article  CAS  Google Scholar 

  7. Liu, B. et al. Glio- and neuro-protection by prosaposin is mediated by orphan G-protein coupled receptors GPR37L1 and GPR37. Glia 66, 2414–2426 (2018).

    Article  Google Scholar 

  8. Inoue, A. et al. TGFα shedding assay: an accurate and versatile method for detecting GPCR activation. Nat. Methods 9, 1021–1029 (2012).

    Article  CAS  Google Scholar 

  9. Zheng, X., Asico, L. D., Ma, X. & Konkalmatt, P. R. G protein-coupled receptor 37L1 regulates renal sodium transport and blood pressure. Am. J. Physiol. Ren. Physiol. 316, F506–F516 (2019).

    Article  Google Scholar 

  10. Foster, S. R. et al. Discovery of human signaling systems: pairing peptides to G protein-coupled receptors. Cell 179, 895–908 (2019).

    Article  CAS  Google Scholar 

  11. Myers, B. R., Neahring, L., Zhang, Y., Roberts, K. J. & Beachy, P. A. Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium. Proc. Natl Acad. Sci. USA 114, E11141–E11150 (2017).

    Article  CAS  Google Scholar 

  12. Morita, N. et al. GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites. Nature 566, 110–114 (2019).

    Article  CAS  Google Scholar 

  13. Rabal, O., Castellar, A. & Oyarzabal, J. Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization. J. Cheminform. 10, 32 (2018).

    Article  Google Scholar 

  14. Castleman, P. N., Sears, C. K., Cole, J. A., Baker, D. L. & Parrill, A. L. GPCR homology model template selection benchmarking: global versus local similarity measures. J. Mol. Graph. Model. 86, 235–246 (2019).

    Article  CAS  Google Scholar 

  15. Zhou, Q. et al. Common activation mechanism of class A GPCRs. eLife 8, e50279 (2019).

    Article  Google Scholar 

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Acknowledgements

We would like to thank R.M. Graham from the Victor Chang Cardiac Research Institute, Australia, for helpful discussions, T. Nettleton from UNSW Sydney for assistance with identifying the cloning error and A. Inoue from Tohoku University for providing the AP–TGF-α constructs and helpful advice. Funding was provided by an NHMRC CJ Martin Early Career Fellowship (1145746 to T.N.), the NIH (R01 AI118985 and R01 GM117424 to I.K.) and a National Heart Foundation Future Leader Fellowship (101153 to N.J.S.).

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Author notes

  1. These authors contributed equally: Tony Ngo, Brendan P. Wilkins, Sean S. So.

Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA

    Tony Ngo, Kirti K. Chahal & Irina Kufareva

  2. Molecular Pharmacology Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia

    Brendan P. Wilkins, Sean S. So, Peter Keov, James L. J. Coleman & Nicola J. Smith

  3. Orphan Receptor Pharmacology Laboratory, School of Medical Sciences, UNSW Sydney, Kensington, New South Wales, Australia

    Brendan P. Wilkins, Sean S. So & Nicola J. Smith

  4. G Protein-Coupled Receptor Laboratory, School of Medical Sciences, UNSW Sydney, Kensington, New South Wales, Australia

    Angela M. Finch

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Contributions

N.J.S., J.L.J.C., S.S.S. and B.P.W. discovered the cloning error. N.J.S., I.K., T.N., B.P.W., S.S.S. and J.L.J.C. devised the experimental plan for correcting the scientific record. T.N., B.P.W., S.S.S., P.K. and K.K.C. performed experiments. A.M.F. assisted with experimental design. N.J.S., I.K. and T.N. wrote the manuscript with input from all of the authors.

Corresponding authors

Correspondence to Irina Kufareva or Nicola J. Smith.

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Source data

Source Data Fig. 1

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Uncropped western blot.

Source Data Fig. 2

Statistical source data.

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Ngo, T., Wilkins, B.P., So, S.S. et al. Orphan receptor GPR37L1 remains unliganded. Nat Chem Biol 17, 383–386 (2021). https://doi.org/10.1038/s41589-021-00748-z

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