Competition between Li+ and Mg2+ for red blood cell membrane phospholipids: A P-31, Li-7, and Li-6 nuclear magnetic resonance study

The mode of action of the lithium ion (Li+) in the treatment of manic depre ssion or bipolar illness is still under investigation, although this inorga nic drug has been in clinical use for 50 yr. Several research reports have provided evidence for Li+/Mg2+ competition in biomolecules. We carried out this study to characterize the interactions of Li+ and Mg2+ with red blood cell (RBC) membrane components to see whether Li+/Mg2+ competition occurs. P-31 nuclear magnetic resonance chemical shift measurements of the phosphol ipids extracted from the RBC membranes indicated that the anionic phospho-l ipids phosphatidylserine and phosphatidylinositol, bind Li+ and Mg2+ most s trongly . From Li-6 relaxation measurements, the Li+ binding constant to th e phospholipid extract was found to be 45 +/- 5 M-1. Thus, these studies sh owed that the phospholipids play a major role in metal ion binding. Li-7 sp in-lattice relaxation measurements conducted on unsealed and cytoskeleton-d epleted RBC membrane in the presence of magnesium indicated that the remova l of the cytoskeleton increases lithium binding to the more exposed anionic phospholipids (357 +/- 24 M-1) when compared to lithium binding in the uns ealed RBC membrane (221 +/- 21 M-1). Therefore, it can be seen that the cyt oskeleton does not play a major role in Li+ binding or in Li+/Mg2+ competit ion.