Abstract: The structure and function of nAChRs,ligand-binding sites,gating mechanism and interactions with neonicotinoids were reviewed.Effects of mutations and knockout of subunit genes on the sensitivity to neonicotinoids and spinosad were also discussed.The nAChRs play an essential role in the fast excitatory neurotransmission at cholinergic synapses in both vertebrates and insects.However,nAChRs are confined to the central nervous system (CNS) in insects,unlike in vertebrates where they are also found in neuromuscular junctions.The nAChRs are the target site for the neonicotinoids,spinosad ,as well as cartap.The nAChR,both in muscle and CNS,is a heteromeric pentamer composed of five subunits,typically 2 α and 3 non-α (β,γ and δ).The receptor has three main parts: a region found outside of the cell (extracellular),a region located within the membrane (transmembrane),and an intracellular portion (cytoplasmic).Each of the five subunits is composed of (from N-C terminus) an extracellular domain that includes the acetylcholine (ACh) binding site,four transmembrane domains (M1- 4) with M2 contributing most of the amino acids that line the ion channel,a cytoplassmic loop and an extracellular C-terminus.The channel's gate is expected to located in hydrophobic regions within the pore.The ACh binding site,in native and functional receptors,is located at the interface of two subunits,and possibly composed by three loops (loops A-C) of one subunit and three loops( D-F) of the other subunit.Upon binding the molecules of ACh (or other agonists),the receptor undergoes a conformational change that places the M2 α-helices in the opening,cation-conducting state.The channel remains open before one or both agonist molecules dissociate from the binding pocket and then the channel closes.If the agonist presents and binds repeatedly,the channel would enter a desensitized state.The diverse selective interactions of nAChRs with neonicotinoids depend on the structure of neonicotinoids as well as the subunit composition of the nAChRs.