Desensitizing and non-desensitizing subtypes of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in cockroach neurons

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

“…These observations are in line with electrophysiological recordings on isolated P. americana nerves, where in the presence of ACh, nM concentrations of spinosyn stimulate the α-BGTX-sensitive nAChD current, but are without effect at the IMI sensitive nAChN. 65) Thus, spinosyns are not direct agonists, rather they act at an allosteric site to synergistically enhance agonist-mediated nAChR channel activation.…”

“…[61][62][63] Taken together this body of evidence has led to the suggestion that IMI and α-BGTX have distinct high affinity binding sites. 64,65) hornworm), Heliothis virescens (tobacco budworm) and Ctenocephalides felis (cat flea). This intriguing observation was suggested to explain why IMI is particularly useful for controlling sap-feeding insects.…”

“…66,71) The effects of including detergent are complex and not easily rationalised but low μM concentrations of Triton may interfere with [ 3 H]-IMI binding. 62,65) It has been suggested that two sites for IMI binding maybe the norm, but this certainly requires further evidence for insects outside of the hemipteran order. 67,71,72) Strengthening the idea that hemipteran neonicotinoidresponsive nAChRs display differences compared to other insect orders, Casida applied a photoaffinity-based approach using an azido non-cyclic N-methyl derivative of IMI and demonstrated that the nAChR subunits isolated differed significantly in molecular weight between hemipteran and dipteran insects.…”

“…These neurones possess two pharmacologically distinct components to the nAChR current initiated by ACh application: an initial rapidly desensitising current (nAChD) that peaks within a few hundred milliseconds which is completely blocked by nanomolar application of IMI and a prolonged non-desensitising current (nAChN) which is selectively blocked at sub-nanomolar concentrations by the nAChR antagonist methyllycaconitine (MLA) but activated by micromolar concentrations of IMI. 65) Therefore, the concentration of IMI at the receptor will have a strong influence on the overall neuronal effect, with low nanomolar concentrations appearing to antagonise nAChRs (likely to be more physiologically relevant), whilst rising concentrations cause receptor activation through the stimulation of the α-BGTX sensitive non-desensitising population of nAChRs. 65,93) The exact mechanism by which IMI exerts its effects on insects is clearly a complex issue but is subject to differences in the binding sites presented by different nAChR subtypes and the way that occupancy favours particular conformational states of nAChRs.…”

“…65) Therefore, the concentration of IMI at the receptor will have a strong influence on the overall neuronal effect, with low nanomolar concentrations appearing to antagonise nAChRs (likely to be more physiologically relevant), whilst rising concentrations cause receptor activation through the stimulation of the α-BGTX sensitive non-desensitising population of nAChRs. 65,93) The exact mechanism by which IMI exerts its effects on insects is clearly a complex issue but is subject to differences in the binding sites presented by different nAChR subtypes and the way that occupancy favours particular conformational states of nAChRs. These parameters combined with bioavailability, concentration, distribution and biotransformation (production of active/inactive metabolites) determine delivery of the ultimate pathophysiological effects -anti-feedency and neurotoxicity.…”