Identification of Surface Domains on the Nicotinic Acetylcholine Receptor Molecule by the Use of Antibodies and Toxins

Neurotransmitter receptors are key components for neuronal function. A major breakthrough in the study of these molecules has been provided by cloning and sequencing of their genes. By this approach the amino acid sequence of the precursors of several receptors, among them the GABA receptor (Schofîeld et al., 1987), the glycine receptor (Grenningloh et al., 1987), ß adrenergic receptors (Kubo et al., 1986a, Kubo et al., 1986b, Bonner, et al., 1987) and muscarinic receptors (Yarden et al., 1986, Dixon et al., 1986, Kobilka et al., 1987) from different tissues and different nicotinic receptors (McCarthy et al., 1986, Boulter et al., 1986, Hermans-Borgmeyer et al., 1986, Goldman et al., 1987, Baldwin et al, 1988, Deneris et al., 1988) have been obtained. In the case of receptors which function via a chemically gated ion channel, extensive cloning and sequencing of their genes has led to the intriguing discovery that their molecular structure can be very similar, irrespective of their ion specificity. For example, the sequences of the GABA receptor and the glycine receptor, which both contain an anion (Cl-) gating unit, are very similar to the sequence of the nicotinic receptors (AcChR), which contain a cation (Na+) channel (Schofîeld et al., 1987, Grenningloh et al., 1987). Elucidation of the molecular structure of these receptors is necessary to understand the structural basis for their function and for the ion discrimination operated by these very similar molecules. Regrettably, direct studies of receptor structure by X-ray crystallographic approaches are unsuitable for neurotransmitter receptors, with the possible exception of the nicotinic receptor from Torpedo electric organ, because of their scarcity. New experimental strategies need to be devised to obtain structural information on these molecules, and the available sequence information should be the key towards this endeavour.