Grant: Operating Grant

A heart beat is a cycle of contraction and relaxation of the heart muscle. Contraction occurs when extracellular calcium and calcium located in intracellular membrane stores flows into the muscle cell through calcium channels. Relaxation begins when calcium is pumped out of muscle cells or into internal stores by calcium pumps. If the calcium pumps are maximally active, calcium will be removed from the heart cells at a higher rate and the heart muscle can relax more rapidly and completely. If the internal store is maximally filled by more active calcium pumps, the amount of calcium released into the heart muscle is greater and the force of the subsequent contraction is greater. Calcium pumps in the heart do not always work maximally. They are associated with an inhibitor protein called phospholamban so that calcium pumping activity is reduced sharply. The association between the calcium pump and phospholamban is disrupted, however, when special demands on the body are met by release of adrenalin into the blood. Adrenalin changes the structure of phospholamban so that it can no longer inhibit the calcium pump. Now calcium stores can be loaded with calcium more rapidly and fully so that the heart undergoes a more rapid and complete relaxation and subsequent contractions have greater force. Specific mutations of phospholamban can cause cardiomyopathy. Our laboratory has investigated a mouse line carrying a phospholamban mutation, R9C, which causes dilated cardiomyopathy and premature death in both humans and mice. We have found that the R9C mutation causes changes in the heart that "stress" the ER membrane system which synthesizes secreted proteins and regulates calcium concentrations. In our application, we propose experiments aimed at understanding how the R9C mutation, which alters cellular calcium dynamics, can cause ER stress and how ER stress can alter calcium dynamics. Since ER stress pathway offer many potential drug targets for reversing cardiomyopathy.