Amino acids within loops D, E and F of insect nicotinic acetylcholine receptor beta subunits influence neonicotinoid selectivity

作者：Yao Xiangmei; Song Feng; Chen Fajun; Zhang Yixi; Gu Jianhua; Liu Shuhua; Liu Zewen^*

来源：Insect Biochemistry and Molecular Biology, 2008, 38(9): 834-840.

DOI：10.1016/j.ibmb.2008.05.009

• Nicotinic acetylcholine receptor
• beta Subunit
• Insect-specific loops D, E and F
• Subunit chimera
• Neonicotinoids selectivity

Nicotinic acetylcholine (ACh) receptors (nAChRs) are ligand-gated ion channels which mediate fast cholinergic synaptic transmission in insect and vertebrate nervous systems. The nAChR agonist-binding site is present at the interface of adjacent subunits and is formed by loops A-C present in alpha subunits together with loops D-F present in either non-a subunits or homomer-forming a subunits. To investigate the mechanism of neonicotinoid selectivity, we have examined the effects of altering insect-specific loops D, E and F in hybrid nAChRs containing insect and mammalian subunits (N1 alpha 1 from the brown planthopper Nilaparvata lugens and 2 from rat). Introduction of the insect-specific loops D, E and F, singly or together. into rat 2 subunit resulted in a leftward shift of the imidacloprid dose-response curves for nAChRs N1 alpha 1-beta 2 chimeras, reflecting decreases in EC50, compared to wildtype nAChRs N1 alpha 1-beta 2. By contrast, the influences on ACh potency were minimal or negligible. The effects of loop D could be interpreted by the earlier findings of Shimomura et al. [2006. Role in the selectivity of neonicotinoids of insect-specific basic residues in loop D of the nicotinic acetylcholine receptor agonist-binding site. Mol. Pharmacol. 70,1255-1263.], in which T77R and E79V were shown to be responsible for neonicotinoid selectivity. In the present study, S131Y(R) and D133N in loop E and T191W and P192K in loop F were found to contribute to the neonicotinoid selectivity of insect-specific loops E and F. These results indicated the insect-specific loops D, E and F each play important roles in neonicotinoids selectivity. This study contributes to our understanding of the molecular mechanism underlying selectivity of neonicotinoids against insects over vertebrates.

• 出版日期2008-9
• 单位南京农业大学