Ion channels are membrane proteins that control specific ions moving across cells. Ion movement across the cell membrane results in membrane potential changes, which are used as rapid and accurate signals in organisms. Outward currents through inward rectifier K+ channels (Kir) are important in maintaining stable resting membrane potentials, controlling excitability, and thus regulating physiological processes such as vascular tone, heart rate, renal salt flow, and insulin release. Outward Kir currents increase as [K+]o increases and that elevated outward Kir currents are related to patho-physiological states such as in ischemia, tachycardia, and fibrillation, but the underlying mechanism remains a mystery. We have characterized how outward Kir single-channel currents and their kinetics are modulated by extracellular cations and intracellular polyamines. We are investigating how these regulations of outward Kir currents can be applicable to treatment of arrhythmia. In addition, we use Linkage Analysis based on thermodynamics to characterize and quantitate allosteric interaction of various domains in ion channels. Finally, we are developing photo-activated potassium- and calcium-selective ion channels. After both channel types are constructed, we can switch on and off cell excitability (electrical signals) via optical signals in the brain and heart, thereby allowing us to control functions and understand cell networking in these two types of cells. We anticipate the results of these studies will lead to new research tools and novel therapy interventions for a number of diseases including epilepsy in the brain as well as heart failure and arrhythmia in the heart.