I am fortunate to have been able to study successive generations of novel insecticides invented by many talented scientists in the insecticide industry, which has led to the identification of completely novel target proteins as well as novel targets on already known and exploited target proteins. Nicotinic acetylcholine receptors (nAChRs) are among the oldest insecticide targets. Nicotine extracted from tobacco has been used as a natural organic pesticide for centuries, but it has been largely replaced by the neonicotinoids and other nicotine mimics, which are the largest-selling insecticides today, classified by the insecticide resistance action committee (IRAC) as group 4. Spinosyn insecticides, classified as group 5, activate nicotinic receptors at a site that is allosteric to the orthosteric site where nicotine and its mimics act. IRAC has recently named this nicotinic allosteric modulator site 1 to differentiate it from nicotinic acetylcholine receptor allosteric modulator site 2, the target site of group 32, consisting of the GS-omega/kappa-HXTX-Hv1A peptide.  This classification does not take into account the fact that insects have at least two nAChR subtypes, desensitizing (nAChD) and nondesensitizing (nAChN). Desensitization means that nAChD receptors enter a nonconducting state in the continued presence of agonists, but they in fact remain tightly bound to the agonist, making them very sensitive to the agonist insecticides in IRAC Groups 4A, B, C and D. nAChN receptors, on the other hand, do not desensitize, so they remain open indefinitely in the presence of agonists and have low sensitivity to group 4 insecticides. nAChN receptors have been identified as the target of IRAC group 5 nAChR allosteric modulators, the spinosyns. New results will be presented, showing that mesoionic insecticides (Group 4E) potently and specifically inhibit nAChD receptors as well as a portion (up to 40%) of the nAChN receptors in American cockroach neurons, allowing us to identify a subclass of mesoionic-sensitive nAChN receptors designated nAChNM. nAChNM receptors are insensitive to spinosyns, which appear to activate 100% of the mesoionic-insensitive nAChN receptors, which are accordingly designated spinosyn-sensitive nondesensitizing nicotinic (nAChNS) receptors. Thus, not only are there different target sites on nicotinic receptors, but those sites also occur on different receptor subtypes. The subunit composition of these receptor subtypes is not yet known.

Many faces of nicotinic receptors as insecticide targets

2019 Fall National Meeting

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