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Research ArticleArticle

Membrane Tethered Bursicon Constructs as Heterodimeric Modulators of the Drosophila G Protein–Coupled Receptor Rickets

Benjamin N. Harwood, Jean-Philippe Fortin, Kevin Gao, Ci Chen, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology April 2013, 83 (4) 814-821; DOI: https://doi.org/10.1124/mol.112.081570
Benjamin N. Harwood
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.N.H., J.-P.F., K.G., C.C., M.B., A.S.K.); and Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.N.H., A.S.K.)
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Jean-Philippe Fortin
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.N.H., J.-P.F., K.G., C.C., M.B., A.S.K.); and Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.N.H., A.S.K.)
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Kevin Gao
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.N.H., J.-P.F., K.G., C.C., M.B., A.S.K.); and Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.N.H., A.S.K.)
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Ci Chen
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.N.H., J.-P.F., K.G., C.C., M.B., A.S.K.); and Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.N.H., A.S.K.)
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Martin Beinborn
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.N.H., J.-P.F., K.G., C.C., M.B., A.S.K.); and Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.N.H., A.S.K.)
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Alan S. Kopin
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.N.H., J.-P.F., K.G., C.C., M.B., A.S.K.); and Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.N.H., A.S.K.)
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Abstract

The study of complex heterodimeric peptide ligands has been hampered by a paucity of pharmacological tools. To facilitate such investigations, we have explored the utility of membrane tethered ligands (MTLs). Feasibility of this recombinant approach was explored with a focus on Drosophila bursicon, a heterodimeric cystine-knot protein that activates the G protein–coupled receptor rickets (rk). Rk/bursicon signaling is an evolutionarily conserved pathway in insects required for wing expansion, cuticle hardening, and melanization during development. We initially engineered two distinct MTL constructs, each composed of a type II transmembrane domain, a peptide linker, and a C terminal extracellular ligand that corresponded to either the α or β bursicon subunit. Coexpression of the two complementary bursicon MTLs triggered rk-mediated signaling in vitro. We were then able to generate functionally active bursicon MTLs in which the two subunits were fused into a single heterodimeric peptide, oriented as either α-β or β-α. Carboxy-terminal deletion of 32 amino acids in the β-α MTL construct resulted in loss of agonist activity. Coexpression of this construct with rk inhibited receptor-mediated signaling by soluble bursicon. We have thus generated membrane-anchored bursicon constructs that can activate or inhibit rk signaling. These probes can be used in future studies to explore the tissue and/or developmental stage-dependent effects of bursicon in the genetically tractable Drosophila model organism. In addition, our success in generating functionally diverse bursicon MTLs offers promise that such technology can be broadly applied to other complex ligands, including the family of mammalian cystine-knot proteins.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant 5R01DK070155]. This work was also supported by the Synapse Neurobiology Training Program, National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant T32-NS061764].

  • dx.doi.org/10.1124/mol.112.081570.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received July 27, 2012.
  • Accepted January 22, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (4)
Molecular Pharmacology
Vol. 83, Issue 4
1 Apr 2013
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Research ArticleArticle

Bursicon Membrane Tethered Modulators of Drosophila Rickets

Benjamin N. Harwood, Jean-Philippe Fortin, Kevin Gao, Ci Chen, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology April 1, 2013, 83 (4) 814-821; DOI: https://doi.org/10.1124/mol.112.081570

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Research ArticleArticle

Bursicon Membrane Tethered Modulators of Drosophila Rickets

Benjamin N. Harwood, Jean-Philippe Fortin, Kevin Gao, Ci Chen, Martin Beinborn and Alan S. Kopin
Molecular Pharmacology April 1, 2013, 83 (4) 814-821; DOI: https://doi.org/10.1124/mol.112.081570
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