The nicotinic acetylcholine (ACh) receptors and the other neurotransmitter-gated ion channels have key roles in fast synaptic transmission throughout the nervous system. These receptors have a simple functional repertoire: they bind a specific neurotransmitter, open a gate, conduct specific ions across the membrane, and desensitize. Although it is easy for us to imagine in a general way how they might carry out these steps, to determine the actual mechanism requires more detailed structural information than we now have. Nevertheless, new information about the parts of these receptors that are in the front line of function, the neurotransmitter binding sites, the ion-conducting channel, and the gate, provides intriguing clues, albeit not always consistent ones, about the mechanisms of these receptors. Most progress toward understanding function in terms of structure has been made with the ACh receptors, on which we will focus, at the same time noting what is conserved and what is variable among all of the neurotransmitter-gated ion channels. The ACh receptors are members of a family of neurotransmitter-gated ion channels, which also includes receptors for y-aminobutyric acid (GABA), glycine (Gly), and 5hydroxytryptamine(5HT; Nodaet al., 1983; Grenningloh et al., 1987; Schofieldet al., 1987; Maricqet al., 1991); also in this family is an invertebrate glutamate-gated chloride channel (Gully et al., 1994). The subunits of these receptors have similar sequences and distributions of hydrophobic, membrane-spanning segments and are homologous (Figures 1 and 2). In this family, each subunit contains, in its N-terminal extracellular half, 2 cysteine (Cys) residues separated by 13 other residues. These Cys residues are disulfide linked in the ACh receptor (Kao and Karlin, 1986) and presumably in the homologous receptors, thereby closing a 15-residue loop. Because of this unique, invariant feature, we will call this family the Cys-loop receptors. The subunits of other ligand-gated ion channels-the receptors for glutamate (cation-conducting), for ATP, and for the second messengers, CAMP and cGMP-have sequences and distributions of putative membrane-spanning segments that are dissimilar from those of the Cysloop receptors (Figures 1 and 2). Despite the differences in their structures, all of these ligand-gated ion channels carry out the same general functions. This implies that, at the level of detailed mechanisms, there are many ways of recognizing specific ligands, of transducing binding into propagated structural changes, of gating a channel, and of selecting and conducting specific ions through a membrane. It is likely, however, that among the homologous Cys-loop receptors the mechanisms are very similar and that insight into one is applicable to all.

Overall Structure The path to our understanding function in terms of structure is for us to identify the residues that contribute to ACh binding, to the gate, and to ion-conduction, and to locate these residues in the tertiary structure of their subunits, the subunits in the quaternary structure of the receptor, and the whole structure relative to the plane of the membrane. Ultimately, we must know how the structure changes in going from one functional state to another. As we will discuss later, many of the residues in the binding sites and in the channel are known. It is not yet possible, however, to locate them precisely in three dimensions. Nevertheless, the qualitative location of residues relative to the membrane, the so-called membrane topology of the subunits, and the arrangement of the subunits in the complex are fairly well established for the ACh receptor. Furthermore, Unwin (1993, 1995) solved the …