Ion channels are membrane proteins that allow the selective movement of charged molecules through cellular membranes. Many disease states, such as cystic fibrosis, muscular dystrophies, hypertension, and cardiac arrhythmias are caused by ion channel pathologies. Ion channels have been identified by the drug discovery industry as excellent targets for therapeutic intervention but because of the technical hurdles involved in developing quality, high- throughput functional ion channel assays, the development of ion channel drugs has been disappointing. Photoswitch Biosciences has developed technology, which allows attaching small nanomachines to ion channels enabling rapid and reversible control of these proteins by light. These photoswitched ion channels allow us to non- invasively control cell membrane potential and, hence, the activity of voltage-dependent ion channels. The Specific Aim for the Phase I component of this fast track SBIR project are: (1) Demonstrate the feasibility of using extracellular electric field recording as a membrane potential readout. Our original plan was to use voltage- sensitive dyes for this application, but recent results from our lab suggests that extracellular recording of electrical field potentials may offer a variety of benefits, including instrument design and assay simplicity. The Phase II goals are to build three fully functional prototype screening systems consisting of instruments, engineered cell lines, reagents, and software. The use of the hybrid method of extracellular field potential recording technology coupled with photoswitch technology for ion channel assays has several advantages over existing techniques: (1) Elimination of liquid additions for channel activation, (2) Highly scalable for high-throughput ion channel drug discovery, (3) Price per data point is at least 100X less than automated electrophysiology, (4) Channel activation is almost 100X faster than KCl addition. The ability to rapidly depolarize and repolarize cells in a high-throughput format is especially important for the discovery of use-dependent compounds that achieve target selectivity via affecting only the channels that are active. This breakthrough technology will finally allow the full exploitation of ion channels as drug targets.