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

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

Author information

1
Departments of Pharmacology and Molecular Sciences, Baltimore, MD 21205.
2
Lieber Institute for Brain Development, Baltimore, MD 21205.
3
Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205.
4
Departments of Psychiatry and Behavioral Sciences, Baltimore, MD 21205.
5
Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

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.

PMID:
26879421
PMCID:
PMC4754628
DOI:
10.1038/srep19976
[Indexed for MEDLINE]
Free PMC Article

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