Grant: CIHR New Investigator

Potassium ion channels in cells are essential for healthy hearts. These channels are formed from two different types of proteins. One protein, called Kir6.2, forms the channel pore while the other protein, known as SUR2A, regulates opening and closing of the pore. Proper control of the channel is essential as mutations in the gene for SUR2A cause cardiovascular disorders. We will study the molecular details by which changes in SUR2A cause potassium channels to dysfunction in the heart. SUR2A mutations have many disease-causing defects, including altered ability of SUR2A to sense the cellular concentration of ATP (the energy currency of cells) and the inefficient transport of the channel from where it is made inside the cell to the cell membrane where it functions. These defects result from changes in (1) the 3-D arrangement of atoms in SUR2A, (2) movement of specific regions in SUR2A, and (3) the way that SUR2A interacts with other parts of the channel. Thus, obtaining a 3D picture of SUR2A is critical to understanding cardiovascular diseases. We will focus on the regions of SUR2A that are the sites of disease-causing mutations. These regions, called nucleotide binding domains (NBDs), utilize the energy of ATP to control opening and closing of the pore. Knowledge of the changes in the molecular details of the NBDs caused by the mutations will help develop new treatments for disease. We will use a technique very similar to medical MRI to get a detailed 3D picture of the SUR2A NBDs alone and bound to other parts of the channel. These experiments will also give information regarding how the 3D shape of the NBDs changes in time, which is important for function. We will compare mutants of SUR2A NBDs that cause disease to the SUR2A NBDs in their normal state. These studies promise to enhance our understanding of how SUR2A mutations cause cardiovascular diseases and this molecular level knowledge will help design new molecules to treat disease.