alpha-Conotoxins selectively inhibit one of the two acetylcholine binding sites of nicotinic receptors.

Muscle subtypes of the nicotinic acetylcholine receptor contain two acetylcholine binding sites that can be distinguished pharmacologically. The affinities of several alpha-conotoxins for the two acetylcholine binding sites on nicotinic receptors from BC3H1 cells and Torpedo electric organ were investigated. alpha-Conotoxins MI, GI, and SIA each inhibited the binding of 125I-alpha-bungarotoxin to nicotinic acetylcholine receptors on BC3H1 cells with two distinct and independent affinities, which differed by > 10,000-fold. The affinities of alpha-conotoxins SI and SII were significantly lower and the differences in the affinities of each of these toxins for the two sites were < 400-fold. alpha-Conotoxins MI, GI, SIA, and SI had higher affinity for the acetylcholine binding site near the alpha/delta subunit interface of nicotinic receptors from BC3H1 cells. However, when assessed using nicotinic receptors from Torpedo electric organ, alpha-conotoxin MI displayed higher affinity for the acetylcholine binding site near the alpha/gamma subunit interface. These observations suggest that species variations in the sequences of the gamma and delta subunits resulted in a dramatic reversal of the relative affinities of the alpha-conotoxins for each acetylcholine binding site. Some of the practical implications of these observations are discussed.