title: Schizophrenia-Associated hERG channel Kv11.1-3.1 Exhibits a Unique Trafficking Deficit that is Rescued Through Proteasome Inhibition for High Throughput Screening.
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.
authors.affiliation: Departments of Pharmacology and Molecular Sciences, Baltimore, MD 21205.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Calcaterra
authors.affiliation: Lieber Institute for Brain Development, Baltimore, MD 21205.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hoeppner
authors.affiliation: Lieber Institute for Brain Development, Baltimore, MD 21205.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wei
authors.affiliation: Lieber Institute for Brain Development, Baltimore, MD 21205.|Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Jaffe
authors.affiliation: Lieber Institute for Brain Development, Baltimore, MD 21205.|Departments of Psychiatry and Behavioral Sciences, Baltimore, MD 21205.|Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Brady J
authors.initials: BJ
authors.lastname: Maher
authors.affiliation: Departments of Pharmacology and Molecular Sciences, Baltimore, MD 21205.|Lieber Institute for Brain Development, Baltimore, MD 21205.
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
mesh_terms: D000069286:Bortezomib / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms; D021381:Protein Transport; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D007976:Leupeptins; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; C063261:acetylleucyl-leucyl-norleucinal; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex