BPS2026 – Chemical modulation of the Kv1.2:Slc7a5 channel:transporter complex

Kv1.2 is a prominent voltage-gated potassium channel subtype in the central nervous system, and Kv1.2 mutations are linked to severe neurological diseases including epilepsy. Slc7a5 (also known as LAT1) is a neutral amino acid transporter that is upregulated in many tumor types. Previous reports have identified powerful effects of Slc7a5 on Kv1.2 function and expression. Slc7a5 markedly decreases Kv1.2 expression, hyperpolarizes the voltage-dependence of activation, and inhibits maximal activation of Kv1.2. To investigate the mechanism of Slc7a5 modulation of Kv1.2 expression, we developed a surface labeling assay, and screened the LOPAC1280 library for compounds that could weaken the trafficking effects of Slc7a5, leading to rescue of Kv1.2 cell surface expression. After a primary screen and subsequent validation, we demonstrated that MRS 2159, previously described as a selective P2X1 receptor antagonist, substantially rescued Kv1.2 total expression in the presence of Slc7a5. MRS 2159 did not affect Kv1.2 channels expressed alone. Rather, MRS 2159 rescue was specific for Slc7a5-mediated effects on Kv1.2 expression. Overall, these results identify MRS 2159 as a context-specific modulator that weakens Slc7a5-dependent effects on Kv1.2 expression, providing mechanistic insight and a novel chemical tool to influence channel:transporter modulation.