Schizophrenia-Associated hERG channel Kv11.1-3.1 Exhibits a Unique Trafficking Deficit that is Rescued Through Proteasome Inhibition for High Throughput Screening

Sci Rep. 2016 Feb 16;6:19976. doi: 10.1038/srep19976.

Abstract

The primate-specific brain voltage-gated potassium channel isoform Kv11.1-3.1 has been identified as a novel therapeutic target for the treatment of schizophrenia. While this ether-a-go-go related K(+)channel has shown clinical relevance, drug discovery efforts have been hampered due to low and inconsistent activity in cell-based assays. This poor activity is hypothesized to result from poor trafficking via the lack of an intact channel-stabilizing Per-Ant-Sim (PAS) domain. Here we characterize Kv11.1-3.1 cellular localization and show decreased channel expression and cell surface trafficking relative to the PAS-domain containing major isoform, Kv11.1-1A. Using small molecule inhibition of proteasome degradation, cellular expression and plasma membrane trafficking are rescued. These findings implicate the importance of the unfolded-protein response and endoplasmic reticulum associated degradation pathways in the expression and regulation of this schizophrenia risk factor. Utilizing this identified phenomenon, an electrophysiological and high throughput in-vitro fluorescent assay platform has been developed for drug discovery in order to explore a potentially new class of cognitive therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bortezomib / pharmacology
  • Cell Membrane / metabolism
  • Drug Discovery
  • Ether-A-Go-Go Potassium Channels / chemistry
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Gene Expression
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Intracellular Space / metabolism
  • Leupeptins / pharmacology
  • Mutation
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology
  • Protein Interaction Domains and Motifs
  • Protein Isoforms
  • Protein Transport
  • Schizophrenia / genetics
  • Schizophrenia / metabolism*

Substances

  • Ether-A-Go-Go Potassium Channels
  • Leupeptins
  • Proteasome Inhibitors
  • Protein Isoforms
  • acetylleucyl-leucyl-norleucinal
  • Bortezomib
  • Proteasome Endopeptidase Complex