How neonicotinoids reprogram insect neurons

A new study details the cellular mechanisms triggered by neonicotinoids, a widely used class of insecticides. The research, led by Steeve H. Thany, proposes that these compounds go far beyond simply interacting with membrane receptors.

They activate complex mechanisms of intracellular calcium release, influencing neuronal signaling and possibly contributing to resistance in pests.

Calcium releasing receptors

Nicotinic acetylcholine receptors (nAChRs) in insects function as ion channels.

When activated by neonicotinoids, these channels allow the entry of sodium, potassium and, especially, calcium.

The critical difference compared to the natural neurotransmitter acetylcholine is that the insecticides are not degraded, keeping the channels open for longer. This results in a significant accumulation of calcium inside the cells.

This intracellular increase in calcium triggers a cascade of responses. It includes the activation of kinases such as PKA, PKC, CaMKII and CaMKK, in addition to the mobilization of internal reserves from the endoplasmic reticulum.

The studies used cockroach DUM neurons American Periplaneta to observe these effects in real time.

The neonicotinoid clothianidin, for example, induces a significant increase in calcium, accompanied by changes in membrane potential and neuronal electrical activity.

Variation between compounds and doses

The potency of the effect depends on the type and concentration of the insecticide.

Compounds such as imidacloprid, a partial agonist, activate pathways distinct from those induced by clothianidin, a full agonist.

The concentration also defines which intracellular pathway will be activated: high doses promote cAMP/PKA pathways, while low doses tend to involve PKC or PKG.

The study also suggests that these pathways may be involved in insect resistance to neonicotinoids.

Changes in nAChR subtypes or their phosphorylation sites may interfere with the interaction with kinases, reducing insecticide efficacy. Furthermore, calcium release affects mitochondrial functions, potentially inducing oxidative stress and cellular apoptosis.

Implications for pest control

By understanding these intracellular pathways, it becomes possible to design strategies that enhance the action of insecticides. Combinations with compounds that also increase intracellular calcium - such as diamides - can promote synergism, allowing use in lower doses.

Understanding the specific effects of each substance paves the way for more selective and sustainable products.

According to the author, calcium-regulated pathways are still poorly explored. Future studies should focus on the differential expression of kinases in target tissues and the identification of more sensitive nAChR subtypes. This could redefine insecticide development, reducing impacts on non-target insects and delaying the emergence of resistance.

More information at doi.org/10.1016/j.pestbp.2025.106532