New perspectives on insecticide toxicology and resistance based on neural multireceptor complexes
Author of the article:WAN Yan-Ran1** WANG Mao-Yuan1 CHEN Ke-Wei1 QIAN Kang-Hua2 YANG Hao-Lan2 WU Qing-Jun2***
Author's Workplace：1. College of Plant Protection, Hebei Agricultural University, Baoding 071000, China; 2. State Key Laboratory of Vegetable Biobreeding, Institute of Vegetable and Flower, Chinese Academy of Agricultural Sciences, Beijing 100081, China
Key Words：neural multireceptor complexes; neurotoxic insecticides; signal cross-talk; cross-resistance
Abstract：Neurotoxic insecticides play vital roles in safeguarding global food security and public health, however, their widespread application has triggered the development of pest resistance. Multiple resistance mechanisms have been clarified using the theories of conventional target-site mutation and metabolic detoxification. Nevertheless, the classical "single-target" research paradigm lacks explanatory power for complex phenomena, such as unintended cross-resistance and functional compensation among insecticides with disparate modes of action. This indicates that the insect nervous system possesses more sophisticated target organization patterns and regulatory networks than are currently understood. Neuroscientific research on vertebrates has demonstrated that neural receptors can assemble into functional "multineuroreceptor complexes", which collaboratively regulate neuronal functions through allosteric modulation and signal crosstalk. Given the high evolutionary conservation of nervous systems across species, the present study introduces this theory into insect toxicology and insecticide resistance research. We hypothesize that neurotransmitter receptors assemble into supramolecular complexes via protein- protein interactions to cooperatively govern neuronal activity. By analyzing representative cases of insecticide resistance, this work establishes a novel hypothesis for insect resistance, assembling indirect evidence supporting the existence of functional multineuroreceptor complexes mediating resistance in insects, namely cross-target cross-resistance and functional compensation of neural receptors. A theoretical framework of resistance rooted in the multineuroreceptor complex is postulated: Key insecticide targets within the insect nervous system, including nAChRs, VGSCs, GABARs and GluRs, form an integrative functional receptor network. Continuous selection pressure acting on any single node of this network induces adaptive alterations at that node, the impacts of which propagate to other nodes via intramolecular interactions within the complexes, ultimately generating complex broad-spectrum resistance phenotypes. The multineuroreceptor complex theory offers an innovative perspective for deciphering insecticide modes of action and the evolution of resistance, elevating the research paradigm from the "single-molecule" level to the “systematic network” level. It furnishes a molecular framework to interpret unexpected cross-resistance and functional compensation that cannot be explained by traditional models, pioneers new avenues for future insecticide development, and has important theoretical significance and prospects for the formulation and application of scientific strategies to manage resistance.