A chemogenetic technology using insect Ionotropic Receptors to stimulate target cell populations in the mammalian brain

Abstract

Chemogenetics uses artificially-engineered proteins to modify the activity of cells, notably neurons, in response to small molecules. Although a common set of chemogenetic tools are the G protein-coupled receptor-based DREADDs, there has been great hope for ligand-gated, ion channel-type chemogenetic tools that directly impact neuronal excitability. We have devised such a technology by exploiting insect Ionotropic Receptors (IRs), a highly divergent subfamily of ionotropic glutamate receptors that evolved to detect diverse environmental chemicals. Here, we review a series of studies developing and applying this "IR-mediated neuronal activation" (IRNA) technology with the Drosophila melanogaster IR84a/IR8a complex, which detects phenyl-containing ligands. We also discuss how variants of IRNA could be produced by modifying the composition of the IR complex, using natural or engineered subunits, which would enable artificial activation of different cell populations in the brain in response to distinct chemicals.

Keywords: Chemogenetic tool; IR84a/IR8a complex; Ionotropic Receptors; Phenylacetic acid; Prodrug system.