Cardiovascular potassium channels: From molecular basis to disease therapeutics

Abstract My lab studies the mechanistic basis, and functional consequences, of ion channels, particularly inward rectifier (Kir) and ATP-sensitive (KATP) potassium channels, found throughout the cardiovascular system. Our work integrates studies at multiple levels, from the fundamental molecular basis of channel activity to animal models of pathologies associated with human disease. We are interested in how channels are constructed and function, how they regulate individual smooth and cardiac muscles, and how altered channel function contributes to the pathological consequences of aberrant function in the cardiovascular system. We have developed the capability to purify and to analyze channel proteins structurally, biochemically and functionally. This allows us to develop and address exciting new questions and hypotheses regarding the fundamental basis of Kir and KATP channel activity. KATP channels link metabolism to electrical activity in cardiac and smooth muscle and we have discovered how mutations in these KATP channel genes cause distinct human diseases. Cantu syndrome is caused by gain-of-function in vascular KATP channels, and associated with multiple pathological consequences, including reduced systemic vascular resistance, increased cardiac size and output, persistent fetal circulation, pericardial effusion, lymphedema, decreased vascular compliance and decreased gut motility. Unique cellular and animal models, as well as a unique research clinic, provide the tools for us to explain such features, and to develop appropriate therapies. Our recent work leads us to new hypotheses which will be explored using multiple cell biological and physiological approaches in cells, animals, and humans to reach a full understanding of the nature and role of KATP dependent excitability in regulation of cardiovascular function. These studies form the background to the development of novel pharmacological approaches and of appropriate specific therapies for KATP-dependent pathologies.