Conformational Changes in the Nicotinic Acetylcholine Receptor During Gating and Desensitization

The nicotinic acetylcholine receptor (nAChR) is a member of the important Cys loop ligand-gated ion channel superfamily that modulates neuronal excitability. After they respond to their agonists, their actions are terminated either by removal of ligand or by fast and slow desensitization, processes that play an important role in modulating the duration of conducting states and hence of integrated neuronal behavior. We monitored structural changes occurring during fast and slow desensitization in the transmembrane domain of the Torpedo nAChR using time-resolved photolabeling with the hydrophobic probe 3-(trifluoromethyl)-3-(m-iodophenyl)diazirine (TID). After channel opening, TID photolabels a residue on the δ-subunit’s M2−M3 loop and a cluster of four residues on δM1 and δM2, defining an open state pocket [Arevalo, E., et al. (2005) J. Biol. Chem. 280, 13631−13640]. We now find that photolabeling of this pocket persists during the transition to the fast desensitized state, the extent of photoincorporation...