Structural characteristics of ionotropic glutamate receptors as identified by channel blockade.

The channels of four types of ionotropic glutamate receptor (NMDA receptors and Ca-permeable AMPA receptors of rat brain neurons, and cation-selective receptors from mollusk neurons and insect postsynaptic muscle membranes) and two subtypes of nicotinic cholinoreceptor (from frog neuromuscular junctions and cat sympathetic ganglia) were studied. The structural characteristics of channels determining their susceptibility to blockade by organic mono- and dications were identified. These studies used homologous series of adamantane and phenylcyclohexyl derivatives. These experiments showed that the receptors studied here could be divided into two groups. The first group included the AMPA receptor and the mollusk and insect receptors. These were characterized by the lack of effect on the part of monocations and a strong relationship between the activity of dications and the distance between nitrogen atoms. The second group included the NMDA receptor and both subtypes of the nicotinic cholinoreceptor (muscular and neuronal). Here, conversely, the activity of monocations and dications, regardless of their lengths, were essentially identical. A model for the binding sites of blockers in channels is proposed, which takes these observations into account.