Development Of Ampa Receptor Aptamers

The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate ion channel receptors plays an essential role in the mammalian brain activities such as memory and learning, whereas the excessive receptor activation has been implicated in neurological diseases such as stroke, epilepsy, and amyotrophic lateral sclerosis. Inhibitors against AMPA glutamate receptors are drug candidates for a potential treatment of these neurological diseases. Using systematic evolution of ligands by exponential enrichment (SELEX), we have successfully identified three different classes of aptamers with nanomolar affinity against the GluR2Qflip receptor, a key AMPA receptor subunit that controls the calcium permeability and mediates excitotoxicity. One class is a group of competitive aptamers, which we selected by using NBQX, a classic competitive inhibitor. The highest potency or IC50 value for one of the aptamers in this class reached 30 nM, rivaling any exiting AMPA receptor inhibitors. We have also identified two other classes of aptamers that are differentially selective to different conformations of GluR2Qflip: one class uniquely inhibits the open-channel conformation whereas the other inhibits the closed-channel conformation. As an initial proof-of-principle experiment, our results suggest the possibility of developing aptamers that are nanomolar affinity, water-soluble and highly selective to both an AMPA receptor subunit and a unique receptor conformation. These aptamers are therefore excellent water-soluble templates for design of better inhibitors and better drug candidates against AMPA receptors.