Sources of energy for gating by neurotransmitters in acetylcholine receptor channels

Nicotinic acetylcholine receptors (AChRs) mediate signaling in the central and peripheral nervous systems. The AChR gating conformational change is powered by a low- to high-affinity change for neurotransmitters at two transmitter binding sites. We estimated (from single-channel currents) the components of energy for gating arising frombinding site aromatic residues in the α-subunit.Allmutations reduced the energy (TyrC1>>TrpB≈TyrC2> TyrA), with TyrC1 providing ∼40%of the total. Considered one at a time, the fractional energy contributions fromthe aromatic ringswere TrpB ∼35%, TyrC1 ∼28%, TyrC2 ∼28%, and TyrA ∼10%. Together, TrpB, TyrC1, and TyrC2 comprise an "aromatic triad" that provides much of the total energy from the transmitter for gating. Analysis of mutant pairs suggests that the energy contributions fromsome residues are nearly independent. Mutations of TyrC1 cause particularly large energy reductions because they remove two favorable and approximately equal interactions between the aromatic ring and the quaternary amine of the agonist and between the hydroxyl and αLysβ7.