Probing new components (loop G and the α-α interface) of neonicotinoid binding sites on nicotinic acetylcholine receptors

Neonicotinoid insecticides interact with the orthosteric site on the extracellular ligand binding domain (LBD) of nicotinic acetylcholine receptors (nAChRs), typically activating the cation permeable ion channels. In nAChRs consisting of two alpha and three non-alpha subunits, LBDs contain six loops (loops A, B and C on the alpha subunit and loops D, E and F on the non-alpha subunit) which make up the orthosteric binding site at the alpha/non-alpha subunit interfaces. Recently, an additional site (loop G) on the beta 1 strand has been identified. Also, when the alpha/non-alpha subunit ratio is 3/2, another binding site is generated at the interface of two adjacent alpha subunits. Roles for loop G and the alpha-alpha interface in the interactions with neonicotinoids are discussed with reference to recent structural and physiological data. (C) 2015 Elsevier Inc. All rights reserved.