Examining the relationship between structure and function in voltage-gated ion channels will not only clarify the fundamental mechanisms of cellular excitability, but will also explain how ion channels can malfunction. Ion channel mutations have been linked to disorders ranging from metabolic disturbances to heart arrhythmias, with possible links to epilepsy and other neurological disorders. Understanding the molecular mechanisms of voltage sensitivity in ion channels will not only lead to a better understanding of the electrical communication between neurons, but will also help explain the clinical manifestations of ion channel disorders. Current knowledge of voltage-gated ion channels indicates that different regions of the channel undergo conformational changes with voltage. However, the magnitude of these changes and their effects on channel structure are unknown, as is the tertiary structure of the protein. Measuring distances between different regions of the channel as a function of voltage will help elucidate the conformational changes associated with voltage gating. Fluorescence resonance energy transfer (FRET) has been used to measure the distance between two different fluorescent probes, a donor molecule and an acceptor molecule, by measuring the transfer of energy between the probes. By attaching one probe to a putative voltage-sensing region and the other to a static region of the channel, FRET has the potential to determine which regions of the channel move in response to voltage and the distances traveled by these regions from the closed to the open state of the channel.
