Grant: Operating Grant

Inside of our cells, ion levels are used to control a variety of physiological processes, such as muscle contraction and relaxation. Muscle contraction and relaxation occur as a direct response to oscillations in the cytosolic calcium concentration. To do this, the cell relies on the cyclic release and reuptake of calcium between external and internal stores and the cytosol. In addition, the metabolic processes that allow muscle contraction-relaxation to occur increase the cytosolic proton concentration (acidosis). However, the contractile apparatus in heart muscle is compromised by acidosis. Therefore, the regulated control of both of these ions (calcium and protons) is essential for heart muscle contractility. Calcium metabolism is primarily controlled by the sarcoplasmic reticulum (SR) - a calcium storage compartment containing a pump (SERCA) that plays a central role in muscle relaxation. Additional proteins 'phospholamban' (PLB) and 'sarcolipin' (SLN) regulate SERCA in response to stress, exercise, and disease. Proton metabolism in the heart is primarily controlled by the plasma membrane, which contains a sodium-proton exchanger (NHE1) that removes intracellular protons. Most intriguing is the pathological role of NHE1 in heart disease. The reduced blood flow that occurs in heart disease activates NHE1; however, under disease conditions NHE1 indirectly triggers cell death. Our research encompasses structure-function studies of these calcium and proton transport systems. First, we use membrane reconstitution systems to provide insights into the mechanism of ion transport. Second, we use techniques called 'x-ray crystallography' and 'electron microscopy' that allow us to determine the arrangement of atoms in the proteins from the interaction with a beam of x-rays or electrons (special forms of light). This will provide us with a molecular picture of the ion transporters, and take us one step closer to the rational improvement of heart performance in patients