A diverse group of neurotransmitter receptors are ligand-gated ion channels. These can be subgrouped into receptors that are either excitatory (acetylcholine, glutamate, serotonin) or inhibitory [g-aminobutyric acid (GABA), glycine]; they have similar structural features, but different regulatory properties. These receptors are characterized by fast- and short-acting responses to ligand. Additionally, these receptors are subject to targeting by docking proteins that induce aggregation. The increased permeability to ions results in the influx of second messengers, resulting in activation of downstream targets.
1. Receptor Structure
Because it was one of the first receptors studied in detail, more is known about the nicotinic acetylcholine receptor than any other (1). This receptor consists of four different polypeptide chains, with the composition a2bgd. Each subunit has a single transmembrane domain. Although the structure of the channel is not known, the five subunits are thought to assemble together to form a pore, with the neurotransmitter binding site located in the extracellular domain of the asubunits. Numerous mutational analyses have led to an understanding of the molecular dynamics of the regulation of the channel by ligands. Thus, acetylcholine binding induces a conformational change, opening the gate to allow influx of Na+ and K+ ions (1).
The structures of the inhibitory ligand-gated anion channels are similar to the nicotinic cholinergic receptor. Both GABA and glycine activate Cl- channels, in a manner analogous to the regulation of K+ and Na+ channels by acetylcholine.
2. Regulation of Ligand-Activated Channels
Ligand-activated channels are generally found to be clustered on the postsynaptic side of a synapse. Recent studies have suggested that the clustering is mediated by interactions with a group of targeting proteins, such as PSD-95 and GRIP, that contain PDZ domains. These regions are domains involved in protein-protein interactions and are known to interact with specific sequences in the C-terminal regions of transmembrane proteins (2).
Ligand-gated ion channels are also known to be regulated by phosphorylation. The primary structures of these receptors contain numerous consensus sequences for various protein kinases. Both in vivo and in vitro experiments have demonstrated phosphorylation of both excitatory and inhibitory receptors, by both tyrosine kinases and serine/threonine kinases. These phosphorylations are likely to play a role in modulating the activation of the receptor by ligands, and they may have consequences for understanding long-term modulation of receptor function (3).
