Examination of the Molecular Mechanisms of Mosquito Odorant Receptors

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The olfactory system of mosquitoes has been targeted as a means to decrease the spread of mosquito borne diseases, including malaria, dengue hemorrhagic fever, and West Nile encephalitis. In this sensory modality, volatile compounds known as odorants initiate depolarization of olfactory receptor neurons (ORNs), which are housed within chemosensory sensilla on the olfactory appendages. Odorant recognition is mediated through several mechanisms, one of which centers on a diverse family of odorant receptors (ORs) expressed on the surface of ORNs. ORs are believed to be responsible for recognizing specific odorants and initiating the depolarization of ORNs. In mosquitoes, the functional unit of OR-based odorant detection consists of a highly- conserved co-receptor, Orco, and a divergent OR associated with odorant specificity. It was previously believed that insect ORs acted as G-protein coupled receptors, similar to vertebrate ORs. However, it now appears that insect OR complexes function as ligand- gated ion channels, but the current mechanistic model remains unclear. Furthermore, the functional significance of conserved residues has yet to be determined. The proposed studies will focus on the ORs of the principal Afrotropical malaria vector mosquito, Anopheles gambiae. The proposed research plans to investigate the channel properties of various Anopheles gambiae OR (AgamOR) complexes using patch clamp electrophysiology. In addition, mutational studies to identify residues critical to various aspects of AgamOR function will also be performed. While the experimental focus of these studies will be on AgamOR structure/function, we expect that the molecular model derived from the proposed experiments will be broadly applicable to other insect OR complexes.