High Throughput Screening for Specific Inhibitors and Modulators of A Novel Potassium Channel KCNH2 3.1 Associated with Risk for Schizophrenia and its treatment Abstract A recently discovered KCNH2 3.1 potassium channel, a brain selective isoform of the hERG1 potassium channel, has been shown to be increased in the brains of patients with schizophrenia, a genetic risk factor for the emergence of schizophrenia and to affect neuronal cell activity and brain physiology. Because many available antipsychotic drugs bind to know Herg1 channels, the discovery of the novel isoform offers a potential new target for the development of antipsychotic drugs without cardiac side effects. This proposal will use the available Herg1 channel high throughput thallium flux assay to screen compounds for channel modulating activity in a cell line expressing the novel isoform of the hERG channel. The wild type hERG channel will also be screened in parallel to help define the selective modulators of this KCNH2 3.1 potassium channel. The resulting compounds will be validated in electrophysiology experiments. The availability of animal models will allow future testing in vivo for effects on memory and other aspects of animal physiology linked with psychosis.
Title: High Throughput Screening for Specific Inhibitors and Modulators of A Novel Potassium Channel KCNH2 3.1 Associated with Risk for Schizophrenia and its treatment Narrative Drugs that inhibit the neurotransmitter dopamine are the primary medical treatments for psychosis, but none are consistently effective and side effects are major obstacles for ongoing therapy. Many antipsychotic drugs also bind to potassium ion channels and some have cardiac side effects because of this property. Recent genetic studies have identified a new form of the KCNH2 potassium channel that is not found in the heart but is associated with increased risk for schizophrenia and that is increased in the brains of patients with schizophrenia. These recent findings raise the possibility that this new potassium channel may be a target for the development of new therapies. The purpose of the project proposed in this grant application is to identify novel compounds that affect the function of this newly discovered channel via high- throughput screening, and confirmation in secondary assays. Molecules identified by these efforts will help elucidate the role of this channel in disease as well as serve as starting points for development of new medicines for patients suffering from schizophrenia.