Genome wide screening of transmembrane accessory subunits of ion channels

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DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 06: Enabling technologies and specific Challenge Topic Breakthrough technologies for neuroscience (06-NS-103). The title of this proposal is "Genomewide screening of transmembrane accessory subunits of ion channels". Ion homeostasis in organs (e.g., brain, heart, kidney, gastrointestinal tract, etc.) plays critical roles in human and its dysregulation causes lethality or serious disorders. Ion homeostasis is controlled by ion regulators, which include ion channels, transporters, and pumps. Because these proteins may represent drug targets to treat disease and disorders, extensive work has been carried out using genomic approaches to identify pore-forming or catalytic subunits of ion regulators at the molecular level via expression cloning using activity or homology searches. Cloned pore-forming channel subunits overexpressed in heterologous cells exhibit channel activity. However, differences in channel properties observed between recombinant and native channels have been reported for many channels, which were explained by the identification of accessory subunits recently (Jackson and Nicoll, 2009; Tigaret and Choquet, 2009). The existence of accessory subunits severely complicates the study of ion regulators, as the properties and pharmacology of ion regulators with accessory subunits are different. Furthermore, identification of novel accessory subunits burdens researchers with the cumbersome and time-consuming task of characterizing ion regulators by expressing pore-forming or catalytic subunits alone in heterologous cells. To overcome this limitation in the study of ion regulators, we would like to propose a systematic and genome wide screening method to identify transmembrane regulators/accessory subunits of ion channels. Because the human genome encodes more than 1,500 ion regulators, we believe that the successful development of the proposed screening method will impact a broad field of research pertaining to various organ systems and diseases caused by the dysregulation of ion homeostasis. Furthermore, this innovative approach to identify channel accessory subunits provides a new tool to understand the functioning and regulation of ion channels. Because alterations in many ion channels cause human disorders, which are termed channelopathies, we may identify new drug targets for these diseases. Furthermore, channelopathies affect not only the brain but also other tissues, which include the kidney, muscle, and heart. Therefore, the establishment of this approach will impact and stimulate a broad area of research pertaining to ion regulators. PUBLIC HEALTH RELEVANCE: We here propose a simple, but novel, approach to identify novel channel subunits systematically using a genome-wide screening approach. Because alterations in many ion channels cause human disorders, which are termed channelopathies, we may identify new drug targets for these diseases. Furthermore, channelopathies affect not only the brain but also other tissues, which include the kidney, muscle, and heart.