Lithium Transport in Major Affective Disorders: A Model System for Membrane-Plasma and Genetic-Physiologic Interactions

Abstract

As mentioned in the introduction to this symposium and in Dr. Duhm’s paper, there appear to be both genetic and physiologic influences on the rate of sodium-dependent lithium efflux in human red blood cells (RBCs). We have been interested in biological measurements for diagnosing and treating patients with major affective disorders, but are still quite far from the time when we will be able to use this or any biological marker for definitively diagnosing or predicting treatment response. Our investigations have begun to unravel several physiologic and genetic influences on this measurement, a necessary prerequisite for its clinical application. Our findings of the observed influences on lithium transport suggest its use as an example of a sodium-dependent membrane function that can be influenced by both genetic and physiologic parameters (Fig. 1). Genetic factors control the amount of synthesized peptide, its primary structure, and hence its efficiency in catalyzing the exchange of sodium and lithium across the RBC membrane. Membrane factors not directly under genetic control are the rate of cell membrane turnover and the composition of the nonprotein portion of the membrane. From the plasma side of the membrane we see the influence of a variety of externally-associated factors ranging in size from very small molecules, such as peptides and steroid hormones, to very large lipoprotein complexes known to be in active, dynamic equilibrium with the lipoprotein components of the RBC membrane (1). Transfer proteins also regulate membrane structure and function by controlling the rate of incorporation of plasma components into the cell membrane (2). This model attempts to describe the RBC membrane as a dynamic entity, which, although it has certain stable genetically-controlled properties, is susceptible to a number of time-dependent physiologic perturbations that may either increase or decrease the relative rate of ion transport, and hence affect intracellular to extracellular ion distribution ratios. Using this model system we can explore these interactions, their relationship to the ion balance of the cell, and their potential clinical significance.