Does Presynaptic GSK‐3Beta Signaling Play a Role in Bipolar Disorder: Studies of on Dopamine Transporter (DAT) Coding Variants

Abstract

The dopamine transporter (DAT) terminates dopamine (DA) neurotransmission and has been implicated in several neuropsychiatric disorders, including bipolar disorder (BPD). The protein kinase B (Akt)/glycogen synthase kinase (GSK)‐3β pathway has been implicated in the control of DAT‐mediated trafficking/efflux. We reasoned that a direct connection between DAT and DAT regulation via Akt/GSK‐3b pathways could help link genetic associations and the pharmacotherapy of BPD, e.g. with the GSK‐3β inhibitor Lithium. The current study examines the regulation of wildtype DAT and two bipolar associated‐DAT coding variants, A559V and E602G, by the AKT‐dependent GSK3β signaling pathway. Initial studies with the GSK‐3β inhibitor SB216763 (0.1uM‐10uM) to human embryonic kidney 293 cells stably expressing wildtype, epitope‐tagged hDAT induced an increase in DAT trafficking as well as increased [3H] DA uptake, as assessed by biotinylation studies and transport assays. Treatment with BIO, a GSK3β inhibitor, also led to increased DA uptake in A559V transfected cells but decreased DA uptake in E602G transfected cells. Current studies are aimed at a further examination of mutation‐induced differences in wildtype and mutant DAT regulation through the Akt/GSK‐3β pathway and their structural basis. Supported by NIH grant #T32NS06120106.