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.
Highlights
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
Single nucleotide polymorphisms (SNPs) in the second intron of the KCNH2 gene have been associated with an increased risk of schizophrenia[5]
The most apparent issue is channel homology to Kv11.1-1A, the primary channel involved in cardiac IKr currents and frequent anti-target causing arrhythmia, Long QT Syndrome, and torsades de pointes10. hERG channels have been implicated in processes such as midbrain dopaminergic bursting and epilepsy, which may present unique challenges as Kv11.1-3.1 and Kv11.1-1A channels are expressed at similar levels in the brain and have been shown to form heterotetramers in cell models[5,8,11,12]
Summary
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. Meta-analysis of independent clinical association data sets have shown an association of these SNPs, with schizophrenia-relevant phenotypes, such as: lower IQ score, slower cognitive processing speed, decreased hippocampus gray matter volume, altered memory task fMRI signals, and positive patient response to olanzapine[6] These risk-associated alleles associate with increased expression of a novel KCNH2 transcript, KCNH2-3.1, identified via mRNA characterization of post-mortem human brain tissues, suggesting a possible biological mechanism for the clinical associations[5]. To develop novel modulators of this channel for psychiatric indications, great care must be taken to identify molecules with selectivity over the
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