Mapping Methamphetamine-Induced Changes in the GIRK Channel Interaction Proteome

G protein-gated inwardly rectifying potassium (GIRK) channels are widely expressed in the brain and mediate GPCR-dependent slow inhibition. Malfunctioning and dysregulation of GIRK channels can result in various neurological and psychiatric disorders. Drugs of abuse can cause sustained alterations in GIRK function and trafficking in different brain regions, including the medial prefrontal cortex (mPFC), hippocampus and ventral tegmental area (VTA), important nodes in the brain reward pathway. In order to identify new therapeutic targets and develop more effective treatments for drug addiction, it is critical that we understand the molecular mechanisms behind such drug-induced plasticity. Our goal is to use the novel in vivo iBioID technique to define the GIRK channel interaction proteome (i.e., proteins in close proximity to GIRK channels in vivo) to discover novel regulators of GIRK channel function and trafficking. Furthermore, we will investigate how psychostimulant drugs such as methamphetamine alter the GIRK interaction proteome in a regional and cell type-specific manner. We expect to identify a few candidate proteins whose interaction with GIRK channels is modulated by repeated methamphetamine exposure, and we plan to investigate their functional significance with a new R01 grant in the future.