Modulation of Synaptic Transmission by G Protein βγ Subunits

Abstract

Synaptic transmission is characterized by exocytotic events which mediate the release of chemical transmitters to facilitate neuronal communication. Gi/Go coupled GPCRs play an important role in controlling exocytosis. In addition to direct interaction with voltage‐gated calcium channels to inhibit calcium influx, Gβγ subunits bind directly to SNARE proteins in the regulation of fusion events. The current study is aimed at developing small, druglike molecules which target the βγ /SNARE interaction to elucidate details involved in this novel mode of neuromodulation.Compound libraries were screened using a novel, label free detection method, Corning Epic®, which identifies protein‐protein interactions as changes in the local index of refraction due to binding events. Using these signals, we evaluated the ability of small molecules to modulate the Gβγ /SNARE interaction. Initial screening identified five lead compounds. By further application of an iterative analog library synthesis approach, we will develop analogs with improved physiochemical properties to serve as tools to dissect the therapeutic relevance of the Gβγ /SNARE interaction. This work was supported by the National Institutes of Health (EY010291).