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Research ArticleArticle

RNA Aptamer-Based Functional Ligands of the Neurotrophin Receptor, TrkB

Yang Zhong Huang, Frank J. Hernandez, Bin Gu, Katie R. Stockdale, Kishore Nanapaneni, Todd E. Scheetz, Mark A. Behlke, Andrew S. Peek, Thomas Bair, Paloma H. Giangrande and James O. McNamara II
Molecular Pharmacology October 2012, 82 (4) 623-635; DOI: https://doi.org/10.1124/mol.112.078220
Yang Zhong Huang
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Frank J. Hernandez
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Bin Gu
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Katie R. Stockdale
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Kishore Nanapaneni
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Todd E. Scheetz
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Mark A. Behlke
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Andrew S. Peek
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Thomas Bair
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Paloma H. Giangrande
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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James O. McNamara II
Department of Neurobiology (Y.Z.H.) and Department of Pharmacology and Cancer Biology (B.G.), Duke University Medical Center, Duke University, Durham, North Carolina; Department of Internal Medicine (F.J.H., K.R.S., P.H.G., J.O.M.), Center for Bioinformatics and Computational Biology (K.N., T.E.S.), Department of Biomedical Engineering (K.N., T.E.S.), and Department of Ophthalmology and Visual Sciences (T.E.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Integrated DNA Technologies, Coralville, Iowa (M.A.B., A.S.P.); and DNA Facility, University of Iowa, Iowa City, Iowa (T.B.)
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Abstract

Many cell surface signaling receptors, such as the neurotrophin receptor, TrkB, have emerged as potential therapeutic targets for diverse diseases. Reduced activation of TrkB in particular is thought to contribute to neurodegenerative diseases. Unfortunately, development of therapeutic reagents that selectively activate particular cell surface receptors such as TrkB has proven challenging. Like many cell surface signaling receptors, TrkB is internalized upon activation; in this proof-of-concept study, we exploited this fact to isolate a pool of nuclease-stabilized RNA aptamers enriched for TrkB agonists. One of the selected aptamers, C4-3, was characterized with recombinant protein-binding assays, cell-based signaling and functional assays, and, in vivo in a seizure model in mice. C4-3 binds the extracellular domain of TrkB with high affinity (KD ∼2 nM) and exhibits potent TrkB partial agonistic activity and neuroprotective effects in cultured cortical neurons. In mice, C4-3 activates TrkB upon infusion into the hippocampus; systemic administration of C4-3 potentiates kainic acid-induced seizure development. We conclude that C4-3 is a potentially useful therapeutic agent for neurodegenerative diseases in which reduced TrkB activation has been implicated. We anticipate that the cell-based aptamer selection approach used here will be broadly applicable to the identification of aptamer-based agonists for a variety of cell-surface signaling receptors.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS056217]; and by a postdoctoral fellowship from the American Heart Association (to F.J.H.).

  • Duke University (B.G. and Y.Z.H.) and the University of Iowa (J.O.M., F.J.H., and P.H.G.) have applied for a patent on this technology. M.A.B. is employed by Integrated DNA Technologies, Inc. (IDT), which offers oligonucleotides for sale that are similar to some of the compounds described in the article. IDT, however, is not a publicly traded company, and M.A.B. does not personally own any shares/equity in IDT.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.078220.

  • ABBREVIATIONS:

    CNS
    central nervous system
    BDNF
    brain-derived neurotrophic factor
    ECD
    extracellular domain
    SELEX
    systematic evolution of ligands by exponential enrichment
    E18
    embryonic day 18
    HEK
    human embryonic kidney
    PCR
    polymerase chain reaction
    DPBS
    Dulbecco's phosphate-buffered saline
    SPR
    surface plasmon resonance
    BSA
    bovine serum albumin
    PAGE
    polyacrylamide gel electrophoresis
    p
    phospho
    FAM
    fluorescein amidite
    FITC
    fluorescein isothiocyanate
    LDH
    lactate dehydrogenase
    KA
    kainic acid
    AP
    anteroposterior
    ML
    mediolateral
    DV
    dorsoventral
    PBS
    phosphate-buffered saline
    EEG
    electroencephalogram
    shRNA
    short hairpin RNA
    Scr
    scrambled
    ANOVA
    analysis of variance
    MK-801
    5H-dibenzo[a,d]cyclohepten-5,10-imine
    RTK
    receptor tyrosine kinase.

  • Received February 9, 2012.
  • Accepted June 29, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Research ArticleArticle

Functional RNA Ligands for TrkB

Yang Zhong Huang, Frank J. Hernandez, Bin Gu, Katie R. Stockdale, Kishore Nanapaneni, Todd E. Scheetz, Mark A. Behlke, Andrew S. Peek, Thomas Bair, Paloma H. Giangrande and James O. McNamara
Molecular Pharmacology October 1, 2012, 82 (4) 623-635; DOI: https://doi.org/10.1124/mol.112.078220

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Research ArticleArticle

Functional RNA Ligands for TrkB

Yang Zhong Huang, Frank J. Hernandez, Bin Gu, Katie R. Stockdale, Kishore Nanapaneni, Todd E. Scheetz, Mark A. Behlke, Andrew S. Peek, Thomas Bair, Paloma H. Giangrande and James O. McNamara
Molecular Pharmacology October 1, 2012, 82 (4) 623-635; DOI: https://doi.org/10.1124/mol.112.078220
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