Modulation of Neuronal Activity by Synthetic Activators of Lipid-Gated TRPC Channels

Abstract

Transient receptor potential canonical (TRPC) cation channels are highly expressed in the central nervous system. Neuner et al. showed an inverse correlation between TRPC3 expression/activity and firing of hippocampal neurons. These results lead to the concept of TRPC3 being crucially involved in regulation of hippocampal excitability and constitution of fear memory.A small molecule TRPC3/6 agonist GSK1702934A has recently been introduced as a tool to activate lipid-sensitive TRPC channels directly, bypassing phospholipase C signaling. In an attempt to test the potential and pharmacological value of TRPC3 as a direct pharmacological target for interference with hippocampal functions, we characterized the effects of a series of novel synthetic TRPC3 activators, including molecules that are suitable for optical control of agonist activity. All compounds that proved effective in eliciting TRPC3 conductances in TRPC3 overexpressing, but not in wild type HEK293 cells, significantly reduced firing frequency in hippocampal neurons. Experiments with selective TRPC channel inhibitors as well as TRPC knock down strategies confirmed direct modulation of lipid-sensitive TRPC channels by small molecule activators as a suitable basis for pharmacological and/or optopharmacological interventions to govern neuronal functions.Supported by FWF, DK-MCD.