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Molecular Bases of Differential Sensitivity of Sodium Channels to Neurotoxins

The availability of a large number of functionally and pharmacologically diverse sodium channel variants (generated by alternative splicing and RNA editing) represents a great resource to understand the molecular basis of differential sensitivity of sodium channels to various neurotoxins. Currently we are studying the effects of the following insecticides and polypeptide toxins from venoms of scorpions and sea anemones for this project.

Pyrethroid insecticides

We are continuing the molecular and functional analysis of pyrethroid-hypersensitive and pyrethroid-resistant sodium channel variants from different insect and arachnid species with the goal of identifying amino acid residues that could provide new insights into the mechanisms of pyrethroid action and resistance.

Sodium channel blocker insecticides (SCBIs)

Indoxacarb and metaflumizone represent a new class of sodium channel-targeting insecticides known as sodium channel blocker insecticides (SCBIs). SCBIs block sodium channels in a state-dependent manner, similar to therapeutic drugs and local anesthetics. However, we recently showed the receptor site of SCBIs on insect sodium channels may be different from the receptor site of local anesthetics. Consequently, we are taking several different approaches to identify the molecular determinants on insect sodium channels that are critical for the binding and action of SCBIs.

Polypeptide toxins from venoms of scorpions and sea anemones

Insect sodium channels are more sensitive to certain scorpion toxins than mammalian sodium channels. In collaboration with the laboratories of Mickey Gurevitz and Dalia Gordon (Tel-Aviv University, Israel) and Rong Gao (Nanjing Medical University, China), we are characterizing the interactions between scorpion toxins and sodium channels at the molecular level. Our approach is based on the ability of anti-insect selective toxins to differentiate between sodium channel targets in insects and mammals, and aims to clarify the molecular details of the interaction surfaces of the toxins and their receptors.