[Coordination chemogenetics for regulation of glutamate receptors in neuron]

Transmembrane receptors transmit extracellular information into cells. In many cases, protein families are composed of highly homologous subtypes, each of which has unique cellular functions. Therefore, it is highly desired for understanding the physiological roles of the receptor in tissues or animals. However, it is difficult to control the activity of receptors in a cell-type- and subtype-specific manner with high temporal resolution using traditional pharmacological or genetic engineering methods. Recently, chemogenetics has been focused on controlling the cellular signaling in a cell-type-specific manner, which allows for elucidating the function of specific cell types with high temporal resolution. However, conventional chemogenetics are not suitable for understanding the roles of each receptor. Therefore, we have developed a chemogenetic method, termed coordination chemogenetics, in which coordination chemistry and genetic engineering are combined. The coordination chemogenetics enabled artificial activation of ionotropic glutamate receptor (GluA2) and metabotropic glutamate receptor (mGlu1). A palladium (Pd) complex successfully activated mGlu1 in mGlu1(N264H) knock-in mice, demonstrating that endogenous mGlu1 activation is sufficient to evoke a key cellular mechanism of synaptic plasticity that underlies motor learning in the cerebellum. We also expanded the coordination chemogenetics for orthogonal activation of mGlu1 activity using Cu²⁺, Zn²⁺, and Pd complexes for analyzing the individual roles of mGlu1 simultaneously. Notably, coordination chemogenetics can be expanded to apply selective inhibition of transmembrane receptors, and the dissociation is much slower than that of conventional inhibitors. Thus, coordination chemogenetics would be a unique method for controlling mGlu1 in a cell-type-specific manner.