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

The mode of action of the lithium ion (Li⁺) in the treatment of manic depression or bipolar illness is still under investigation, although this inorganic 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. ³¹P nuclear magnetic resonance chemical shift measurements of the phospholipids extracted from the RBC membranes indicated that the anionic phospholipids, phosphatidylserine and phosphatidylinositol, bind Li⁺ and Mg²⁺ most strongly. From ⁶Li relaxation measurements, the Li⁺ binding constant to the phospholipid extract was found to be 45±5M⁻¹. Thus, these studies showed that the phospholipids play a major role in metal ion binding. ⁷Li spin-lattice relaxation measurements conducted on unsealed and cytoskeleton-depleted RBC membrane in the presence of magnesium indicated that the removal of the cytoskeleton increases lithium binding to the more exposed anionic phospholipids (357±24 M⁻¹) when compared to lithium binding in the unsealed RBC membrane (221±21 M⁻¹). Therefore, it can be seen that the cytoskeleton does not play a major role in Li⁺ binding or in Li⁺/Mg²⁺ competition.