The ionic composition inside cells and organelles is precisely controlled and is essential for their proper function. However, the lipid membranes that surround them are energy barriers that charged ions must cross to get from one side to the other. One way that ions traverse this greasy membrane is by diffusing through gated channels composed of proteins that essentially form aqueous pores across the membrane. Although we have interests in many kinds of ion channels, our main interest is devoted to channels that transport chloride ions. It is possible that more people have been killed by diseases that affect chloride channels than any other disease, because cholera, diarrheal diseases of infancy, and cystic fibrosis involve chloride channel function. Chloride channels are essential for fluid and salt secretion from epithelia, play roles in sensory transduction, regulate both cytosolic pH and the pH of intracellular organelles, control neuronal and cardiac excitability, and contribute to bone resorption by osteoclasts. One chloride channel family of ten genes called TMEM16 or ANO is particularly interesting to us because they are linked to a diverse spectrum of human diseases including at least two types of muscular dystrophy (LGMD2L and MMD3, ANO5), spinocerebellar ataxia (SCAR10, ANO10), dystonia and febrile seizures (ANO3), a bleeding disorder (Scotts Syndrome, ANO6), and cancer (ANO1, ANO7, ANO9). Although it was initially believed that all 10 ANO genes encoded chloride channels, we were recently surprised to find that the family is functionally diverse. Some ANOs are chloride channels, while others are thought to be channels that transport lipids between the leaflets of the membrane bilayer. We are interested in understanding how these proteins work on a molecular level: how are they activated and how do they conduct their substrates, ions and/or lipids? We are also interested in how mutations in these proteins produce human disease, particularly ANO5 muscular dystrophies. We are using stem cells from ANO5 patients as well as genetically engineered muscle cell lines to investigate how ANO5 mutations affect muscle cell biology.