Voltage-dependent and -independent Block of α-amino-3-hydroxy-5-methylisoxazole-4-propionate Receptor Channels

Polyamine-containing toxins and synthetic dicationic derivatives of adamantane and phenylcyclohexyl selectively antagonize Ca(2+)-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor channels. These compounds demonstrate voltage-dependent open-channel block and are trapped by closed channels. In this study, we describe an alternative mechanism of non-competitive AMPA receptor inhibition caused by 9-aminoacridine and some of its derivatives. These compounds exhibit similar potency against Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors. The inhibition is largely voltage-independent, binding and unbinding do not require presence of agonist. We conclude that 9-aminoacridine binds to a shallow site in the AMPA receptor, which is located above the activation gate. A comparison of three-dimensional structures of the antagonists suggests that the 'V-like' shape of the hydrophobic headgroup favors voltage-dependent binding to the deep site in the channel pore, whereas the compounds possessing flat aromatic headgroups preferably bind to the shallow site. The characterization of the novel mechanism of AMPA receptor channel antagonism opens a way to develop a new family of pharmacological agents, which can be of scientific and practical importance.