Amino acids within loops D, E and F of insect nicotinic acetylcholine receptor β subunits influence neonicotinoid selectivity
2008
Yao, Xiangmei | Song, Feng | Chen, Fajun | Zhang, Yixi | Gu, Jianhua | Liu, Shuhua | Liu, Zewen
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 α subunits together with loops D-F present in either non-α subunits or homomer-forming α 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 (Nlα1 from the brown planthopper Nilaparvata lugens and β2 from rat). Introduction of the insect-specific loops D, E and F, singly or together, into rat β2 subunit resulted in a leftward shift of the imidacloprid dose-response curves for nAChRs Nlα1-β2 chimeras, reflecting decreases in EC50, compared to wildtype nAChRs Nlα1-β2. 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.
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