RT Journal Article
SR Electronic
T1 RNA Aptamer-based Functional Ligands of the Neurotrophin Receptor, TrkB
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.078220
DO 10.1124/mol.112.078220
A1 Yang Zhong Huang
A1 Frank J. Hernandez
A1 Bin Gu
A1 Katie R. Stockdale
A1 Kishore Nanapaneni
A1 Todd E. Scheetz
A1 Mark A. Behlke
A1 Andrew S. Peek
A1 Thomas Bair
A1 Paloma H. Giangrande
A1 James O. McNamara
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/06/29/mol.112.078220.abstract
AB 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 like 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~2nM), 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.