Structure-function analyses of ion channels involved in glutamatergic signaling

Abstract

Glutamatergic neurotransmission is a set of signal cascades that result in propagation of the action potential from the presynaptic to the postsynaptic neuron. There are fast signals controlled by the ionotropic glutamate receptors and slow signals from metabotropic glutamate receptors that lead to downstream opening of the canonical transient receptor potential ion channels (TRPC). TRPC ion channels function is also modulated by inositol triphosphate receptors (IP3R). The function of these proteins has been studied in vivo and in vitro, which has created a general picture of how these receptors function in the CNS, but detailed descriptions of the mechanism of gating of these receptors remains to be described fully. We present structural snapshots of the TRPC3, TRPC6, and IP3R-3 receptors, solved using cryogenic electron microscopy, that can begin to inform different modes of gating modulation as well as a high throughput screening protocol to identify small molecule modulators of GluA2-auxiliary subunit complexes. These data cumulatively inform us about the interactions of different protein domains, lipids, and small molecules that are important for channel function and how small molecules can be identified to help further the study of these channels.