Jadey_2013_J.Gen.Physiol_141_95

A primary target for nicotine is the acetylcholine receptor channel (AChR). Some of the ability of nicotine to activate differentially AChR subtypes has been traced to a transmitter-binding site amino acid that is glycine in lower affinity and lysine in higher affinity AChRs. We studied the effects of mutations of this residue (alphaG153) in neuromuscular AChRs activated by nicotine and eight other agonists including nornicotine and anabasine. All of the mutations increased the unliganded gating equilibrium constant. The affinity of the resting receptor (K(d)) and the net binding energy from the agonist for gating (DeltaG(B)) were estimated by cross-concentration fitting of single-channel currents. In all but one of the agonist/mutant combinations there was a moderate decrease in K(d) and essentially no change in DeltaG(B). The exceptional case was nicotine plus lysine, which showed a large, >8,000-fold decrease in K(d) but no change in DeltaG(B). The extraordinary specificity of this combination leads us to speculate that AChRs with a lysine at position alphaG153 may be exposed to a nicotine-like compound in vivo.