The main goal of this investigation is to advance the understanding of the biological action of lithium by analyzing the binding and transport properties of the Li+ion in human red blood cells (RBCs) by nuclear magnetic resonance (NMR) spectroscopy. Although a great deal of effort has gone into testing the validity of Li+ transport rates and ratios as genetic markers of bipolar disorders, very little attention has been given to the investigation of Li+ interactions in tissues. We propose to investigate at a molecular level how the Li+ ion changes ion binding and membrane dynamics in control RBCs and then establish whether Li+ has the same or a different effect in RBCs from bipolar patients undergoing lithium treatment. The proposed non-invasive NMR methods will test two possible mechanisms of action of lithium: a membrane abnormality hypothesis, and a competitive mechanism between Li+ and Mg2+ for biological ligands. Our preliminary studies indicate that the NMR methods proposed in this study provide new information about Li+ interactions in RBCs. For example, Li+ binding to membrane components in control RBCs and competition between Li+ and Mg2+ for ATP binding sites can be monitored by the proposed methods. Li+ perturbations of ion transport and binding in RBCs may not be directly applicable to brain tissue, which is the site of Li+'s action in bipolar patients. However, Li+ is administrated orally and thus a detailed knowledge of its interaction with blood components is essential for understanding the known toxicity of this drug. The proposed studies will also contribute to a useful and important database of Li+ interactions in RBCs. Moreover, the results of this research will be of a general interest to those investigating biological transport.
