烟碱乙酰胆碱受体及其与新烟碱类相互作用的研究进展

对烟碱乙酰胆碱受体(nAChRs)的结构与功能、配体结合部位、门控机理以及与新烟碱类的相互作用进行了综述,并对nAChRs亚基基因突变和敲除对新烟碱类和多杀菌素敏感性的影响进行了讨论。nAChRs在脊椎动物和昆虫的胆碱能突触的快速神经传递中起着重要作用,其在昆虫中仅存在于中枢神经系统(CNS)中,而在脊椎动物中同时存在于CNS和神经肌肉连接处。nAChRs是新烟碱类杀虫剂、多杀菌素和杀螟丹的作用靶标。肌肉和CNS中的nAChRs是一个由两个α和三个非α(β,γ和δ)亚基组成的异数五聚体,该受体主要有三部分:一个在细胞外发现的区域(胞外区)、一个位于膜内的区域(跨膜区),另一个是位于细胞内的区域(胞质区)。每个亚基(从N-C端)都具有一个包含乙酰胆碱(ACh)结合部位的细胞外结构域;4个跨膜结构域(M1~4),其中M2的大部分氨基酸位于离子通道的内壁;一个胞质噜扑(loop)和一个胞外C端。通道门位于孔道内的疏水区。ACh结合部位位于天然和功能受体的两个亚基的界面,是由一个亚基的3个噜扑(A-C)和另一个亚基的3个噜扑(D-F)构成。每当受体与ACh(或其他激动剂)分子结合时,M2 α螺旋体的构象发生改变,使通道开启,处于阳离子传导状态,直至一个或两个激动剂分子从结合口袋解离,通道才关闭。如果激动剂一直存在,并反复结合,则通道处于脱敏状态。nAChRs与新烟碱类的各种选择性作用取决于新烟碱类的结构以及nAChRs的亚基组成。

Advances in Nicotinic Acetylcholine Receptors and their Interactions with Neonicotinoids

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.