Key result
Proteasome inhibition with bortezomib rescued the trafficking deficit and significantly increased peak tail currents of the schizophrenia-associated Kv11.1-3.1 channel in vitro.
Proteasome inhibition rescues the trafficking deficit of the schizophrenia-associated hERG channel Kv11.1-3.1, enabling high-throughput screening for drug discovery.
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Supports proteasome inhibition to rescue hERG trafficking in vitro; leaves open therapeutic relevance for schizophrenia or cardiac channelopathies.
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.
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Calcaterra et al. (2016) studied Schizophrenia (Kv11.1-3.1 channel deficit). Proteasome inhibition (Bortezomib) vs. Untreated/DMSO control was evaluated on Kv11.1-3.1 channel trafficking efficiency and peak tail currents (p=<0.0001). Proteasome inhibition with bortezomib rescued the trafficking deficit and significantly increased peak tail currents of the schizophrenia-associated Kv11.1-3.1 channel in vitro.
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