Ion channels govern the activity of the thinking brain, beating heart, contracting muscle, and every cell of the body. They are targets of many therapeutic agents; mutations of ion channel genes are the cause of dozens of inherited diseases, including cardiac arrhythmias and neurological illnesses. Many of these ion channels are opened in response to changes in voltage across the cell membrane. The central long-term aim of this proposal is to understand the molecular mechanism of voltage gating of ion channels. We recently discovered an ion channel in bacteria (NaChBac) that has many of the properties of an important class of ion channels in humans: it is selectively permeant to sodium, opened (gated) by changes in membrane voltage, and inactivated in a time-dependant manner after voltage-dependant gating.NaChBac is unique in being the only voltage-dependent ion channel that can be expressed and studied in a mammalian cell line. This is important because bacterial channels are the most likely sources of sufficient protein for high-resolution structural studies (X-ray crystallography). The NaChBac protein has been crystallized and is likely to yield high-resolution structural data. It is thus crucial to investigate the structure and function of this ion channel through a combination of mutagenic and electrophysiologic studies. Information gained about its ion selectivity, voltage gating, and inactivation can then be directly correlated to the structure when obtained. Understanding this relatively simple ion channel will help us understand how the larger class of channels function, and eventually how we might target them with therapeutic agents.
