ALPHA-CONOTOXINS SELECTIVELY INHIBIT ONE OF THE 2 ACETYLCHOLINE BINDING-SITES OF NICOTINIC RECEPTORS

Muscle subtypes of the nicotinic acetylcholine receptor contain two ac etylcholine binding sites that can be distinguished pharmacologically. The affinities of several alpha-conotoxins for the two acetylcholine binding sites on nicotinic receptors from BC(3)H1 cells and Torpedo el ectric organ were investigated. alpha-Conotoxins MI, GI, and SIA each inhibited the binding of I-125-alpha-bungarotoxin to nicotinic acetylc holine receptors on BC(3)H1 cells with two distinct and independent af finities, which differed by >10,000-fold. The affinities of alpha-cono toxins SI and SII were significantly lower and the differences in the affinities of each of these toxins for the two sites were <400-fold. a lpha-Conotoxins MI, GI, SIA, and SI had higher affinity for the acetyl choline binding site near the alpha/delta subunit interface of nicotin ic receptors from BC(3)H1 cells. However, when assessed using nicotini c receptors from Torpedo electric organ, alpha-conotoxin MI displayed higher affinity for the acetylcholine binding site near the alpha/gamm a subunit interface. These observations suggest that species variation s in the sequences of the gamma and delta subunits resulted in a drama tic reversal of the relative affinities of the alpha-conotoxins for ea ch acetylcholine binding site. Some of the practical implications of t hese observations are discussed.