Identification of a binding pocket in mosquito TRPA1 for the natural repellent cinnamodial

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is a receptor of noxious heat and chemicals that has been shown to be a biochemical target for a variety of mosquito repellents (e.g., citronellal, catnip oil). These repellents activate TRPA1 channels in sensory tissues (e.g., antennal sensilla), which then triggers avoidance behaviors in the mosquito. However, the mechanisms by which repellents dock with and activate mosquito TRPA1 channels are not well understood. Here we investigate the mechanism of binding between TRPA1 of Aedes aegypti and cinnamodial (CDIAL), a repellent compound found in plants of the genus Cinnamosma. We found that when Ae. aegypti TRPA1 is expressed in Xenopus laevis oocytes it is potently activated by CDIAL. Moreover, using a site-directed mutagenesis approach, we identified a putative binding pocket for CDIAL in the cytosolic N-terminal domain of Ae. aegypti TRPA1. Our results provide new insights into the interaction between natural product repellents and mosquito TRPA1 channels and may allow for the rational design and discovery of TRPA1 agonists with high specificity for mosquitoes.