Journal article
RNA aptamer-based functional ligands of the neurotrophin receptor, TrkB
Molecular pharmacology, Vol.82(4), pp.623-635
10/2012
DOI: 10.1124/mol.112.078220
PMCID: PMC3463223
PMID: 22752556
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 (K(D) ∼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.
Details
- Title: Subtitle
- RNA aptamer-based functional ligands of the neurotrophin receptor, TrkB
- Creators
- Yang Zhong Huang - Department of Neurobiology, Duke University Medical Center, Duke University, Durham, North Carolina, USAFrank J HernandezBin GuKatie R StockdaleKishore NanapaneniTodd E ScheetzMark A BehlkeAndrew S PeekThomas BairPaloma H GiangrandeJames O McNamara II
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.82(4), pp.623-635
- Publisher
- United States
- DOI
- 10.1124/mol.112.078220
- PMID
- 22752556
- PMCID
- PMC3463223
- ISSN
- 1521-0111
- eISSN
- 1521-0111
- Grant note
- R01 CA138503 / NCI NIH HHS R01 NS056217 / NINDS NIH HHS NS056217 / NINDS NIH HHS
- Language
- English
- Date published
- 10/2012
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Radiation Oncology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979975302771
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