Structural insights into the progressive recovery of α7 nicotinic acetylcholine receptor from nicotine-induced desensitization

Nicotine is the predominant alkaloid in tobacco leaves and affects the human nervous system by interacting with nicotinic acetylcholine receptors (nAChRs). Chronic nicotine exposure leads to nAChR desensitization, while nicotine withdrawal leads to nAChR recovery. However, detailed molecular mechanisms underlying nicotine-induced nAChR desensitization and its recovery remain elusive. Here, we present cryo-EM structures of the α7 nAChR in complex with nicotine in both an open state and multiple desensitized states. Comparative analyses reveal progressive conformational changes during recovery from nicotine-induced desensitization and show that asymmetric nicotine binding disrupts the symmetry of the channel pore at the 16′ and 17′ sites. Integrating these findings with patch-clamp recordings and computational simulations, we identify an agonist-free structure that represents an atypical desensitized state closely resembling the resting conformation of α7 nAChR. These detailed mechanistic studies enhance our understanding of nicotine’s effects on α7 nAChRs.