Molecular basis for control of the heartbeat by Na+

Contraction of the heart is triggered by an increase in Ca2+ within cardiac muscle cells, as Ca2+ ions bind to contractile proteins. The rise in Ca2+ results primarily from release from the sarcoplasmic reticulum which is the main intracellular store of C a2+. Therefore, the pumping ability of the heart is critically dependent on the movement of Ca2+. In heart failure, the pumping ability of the heart is impaired, due to unbalanced Ca2+ homeostasis. In normal heart myocytes, the movement of Ca2+ is related to local 'pockets' under the cell membrane where ions can accumulate and deplete during the cardiac cycle. The existence of these 'ion pockets' is possible since diffusion of ions in the cytosol is slow. In particular, local accumulations of Na+ might be critical since Ca2+ homeostasis is partly regulated by a protein which transports these ions in opposite directions, the Na+/Ca2+ exchanger. The Na+/Ca2+ exchanger primarily removes Ca2+ from the cell, but under certain conditions can bring Ca2+ in as Na + is removed. We hypothesize that this function is dependent on a how local pools of Na+ are controlled in the cell, and on cross-talk between several proteins. For this cross-talk to occur, Na+ handling proteins must be correctly targeted and co-localize d. Thus, the surface membrane and the membrane of the sarcoplasmic reticulum must be in close proximity. This project examines protein anchoring, structure of membranes, and function of membrane proteins that regulate Na+ homeostasis. We will also study s ignal mechanisms and proteins that control the activity of these membrane proteins, and how this multiprotein complex is targeted and kept in place. Finally, we will determine whether altered activity, localization, and regulation of Na+ handling proteins contributes to the unbalanced Ca2+ homeostasis in heart failure. These issues will be addressed through coordinated experiments in partnership with a number of international collaborators.