Research Article| Volume 22, ISSUE 7, P857-871, July 1987

The effect of lithium on the membrane molecular dynamics of normal human erythrocytes

      This paper is only available as a PDF. To read, Please Download here.


      Erythrocytes from normal adults with no personal or family history of bipolar affective disorder were analyzed by fluorescence spectroscopy to determine what effect, if any, acute in vitro incubation with lithium had on erythrocyte membrane dynamics. The effects on erythrocyte membrane molecular dynamics of varying concentrations of Li2CO3 (0.25–2.0 meq/liter), varying incubation temperatures (25–40°C), and varying incubation times (5–185 min) were investigated. Following incubation with Li2CO3, the erythrocytes were labeled with either 4-phenylspiro-[furan-2(3H),−1′phthalan]−3,3′-dione (fluorescamine), which binds to membrane surface primary amines, or 12(9)anthroyl stearate [12(9)AS], which inserts deep in the membrane hydrocarbon core. The membrane molecular dynamics were then determined by fluorescence anisotropy measurements. These studies demonstrate that clinically relevant concentrations of Li+ incubated with intact normal human erythrocytes significantly alters molecular dynamics on the erythrocyte membrane surface, with less striking changes in the hydrocarbon core. A possible interpretation of these findings is that hydrated Li+ alters the electrostatic interaction of membrane surface molecules, as well as the surrounding solvent (water) structure, with a resultant increase in the molecular motion of these molecules. Alterations in membrane receptor motion could potentially alter receptor functional activity. If similar motional alterations were to occur in the interior of a membrane channel, such as an ionophore, the functional activity of the channel could also be potentially altered. These findings provide additional insight into possible biological actions of Li +, as well as potential molecular alterations in bipolar affective disorder erythrocytes.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Cevc G
        • Seddon JM
        • Marsh D
        Thermodynamic and structural properties of phosphatidylserine bilayer membranes in the presence of lithium ions and protons.
        Biochim Biophys Acta. 1985; 814: 141-150
        • Charvolin J
        • Lowenstein A
        • Virlet J
        Cation resonances in a lyotropic system.
        J Magn Reson. 1977; 26: 529-531
        • Cotton Wilkinson
        Advanced Inorganic Chemistry. A Comprehensive Text.
        in: ed 3. John Wiley-Interscience, New York1972: 189-205
        • Dorus E
        • Pandey GN
        • Shaughnessy R
        • Gaviria M
        • Val E
        • Ericksen S
        • Davis JM
        Lithium transport across red cell membrane: A cell membrane abnormality in manic-depressive illness.
        Science. 1979; 205: 932-934
        • Dorus E
        • Pandey GN
        • Schumacher R
        • Davis JM
        Genetic control of lithium transport across the red cell membrane: relationship between cell membrane function and the etiology of affective disorders.
        Biol Psychiatry Today. 1979; : 1143-1147
        • Dorus E
        • Pandey GN
        • Shaughnessy R
        • Davis JM
        Lithium transport across the RBC membrane: a study of genetic factors.
        Arch Gen Psychiatry. 1980; 37: 80-81
        • Dunham PB
        • Senyk O
        Lithium efflux through the Na/K pump in human erythrocytes.
        in: Proc Natl Acad Sci USA. 74. 1977: 3013-3099
        • Fong TM
        • McNamee MG
        Correlation between acetylcholine receptor function and structural properties of membranes.
        Biochemistry. 1986; 25: 830-840
        • Fossel ET
        • Sarasua MM
        • Koehler KA
        A lithium-7 NMR investigation of the lithium ion interaction with phosphatidylcholine-phosphatidylglycerol membranes. Observation of calcium and magnesium ion competition.
        J Magn Reson. 1985; 64: 536-540
        • Greil W
        • Eisenried F
        • Becker BF
        • Duhm J
        Inter-individual differences in the Na+-dependent Li+ countertransport system and in the Li+ distribution ratio across the red cell membrane among Li+ treated patients.
        Psychopharmacology. 1977; 53: 19-26
        • Hauser H
        • Shipley GG
        Crystallization of phosphatidylserine bilayers induced by lithium.
        J Biol Chem. 1981; 256: 11377-11380
        • Hokin-Neaverson M
        • Spiegel DA
        • Lewis WC
        Deficiency of erythrocyte sodium pump activity in bipolar manic-depressive psychosis.
        Life Sci. 1974; 15: 1739-1748
        • Hokin-Neaverson M
        • Burckhardt WA
        • Jefferson JW
        Increased erythrocyte Na+ pump and NaK-ATPase activity during lithium therapy.
        Res Commun Chem Pathol Pharmacol. 1976; 14: 117-126
        • Lindblom G
        Ion binding in liquid crystals studied by NMR III. 23Na quadrupolar effects in a model membrane system.
        Acta Chem Scand. 1971; 25: 2767-2768
        • Linnoila M
        • MacDonald E
        • Reinila M
        • Leroy A
        • Rubinow DR
        • Goodwin FK
        RBC membrane adenosine triphosphatase activities in patients with major affective disorders.
        Arch Gen Psychiatry. 1983; 40: 1021-1026
        • Mendels J
        • Frazier A
        Intracellular lithium concentration and clinical response: Towards a membrane theory of depression.
        J Psychiatr Res. 1973; 10: 9-18
        • Mendels J
        • Frazier A
        Alterations in cell membrane activity in depression.
        Am J Psychiatry. 1974; 131: 1240-1246
        • Ostrow DG
        • Pandey GN
        • Davis JM
        • Hurt SW
        • Tosteson DC
        A heritable disorder of lithium transport in erythrocytes of a subpopulation of manic-depressive patients.
        Am J Psychiatry. 1978; 135: 1070-1078
        • Pandey GN
        • Ostrow DG
        • Haas M
        • Dorus E
        • Casper RC
        • Davis JM
        • Tosteson DC
        Abnormal lithium and sodium transport in erythrocytes of a manic patient and some members of his family.
        in: Proc Natl Acad Sci USA. 74. 1977: 3607-3611
        • Pandey GN
        • Sarkadi B
        • Haas M
        • Gunn RB
        • Davis JM
        • Tosteson DC
        Lithium transport pathways in human red blood cells.
        J Gen Physiol. 1978; 72: 233-247
        • Pandey GN
        • Baker J
        • Chang S
        • Davis JM
        Prediction of in vivo red cell/plasma Li+ ratios by in vitro methods.
        Clin Pharmacol Ther. 1978; 24: 343-349
        • Pandey GN
        • Dorus E
        • Davis JM
        • Tosteson DC
        Lithium transport in human red blood cells.
        Arch Gen Psychiatry. 1979; 36: 902-908
        • Pettegrew JW
        Toward a molecular basis for affective disorders.
        in: Altschuler KZ Rush AJ Diagnosis and Treatment of Depression. Guilford Press, 1985: 183-204
        • Pettegrew JW
        • Nichols JS
        • Stewart RM
        Fluorescent studies of fibroblasts, lymphocytes, and erythrocytes in Huntington's disease.
        Trans Am Neurol Assoc. 1979; 104: 61-66
        • Pettegrew JW
        • Nichols JS
        • Stewart RM
        Membrane studies in Huntington's disease—Steady state fluorescence of intact erythrocytes.
        Ann Neurol. 1980; 8: 381-386
        • Pettegrew JW
        • Nichols JS
        • Stewart RM
        Membrane studies in neuropsychiatry—Fluorescence spectroscopy of intact human fibroblasts, lymphocytes and erythrocytes in genetic disease.
        in: Gerson SH Genetic Strategies in Psychobiology and Psychiatry. Boxwood Press, Pacific Grove, CA1981: 171-185
        • Pettegrew JW
        • Nichols JS
        • Minshew NJ
        • Rush AJ
        • Steward RM
        Membrane biophysical studies of lymphocytes and erythrocytes in manic-depressive illness.
        J Affect Dis. 1982; 4: 237-247
        • Pettegrew JW
        • Minshew NJ
        • Nichols JS
        Fluorescence probes specific for the plasma membrane of intact human erythrocytes and lymphocytes.
        Life Sci. 1982; 30: 1101-1105
        • Pettegrew JW
        • Woessner DE
        • Minshew NJ
        • Glonek T
        Sodium-23 NMR analysis of human whole blood, erythrocytes, and plasma. Chemical shift, spin relaxation, and intracellular sodium concentration studies.
        J Magn Reson. 1984; 57: 185-196
        • Pettegrew JW
        • Post JFM
        • Panchalingam K
        • Withers G
        • Woessner DE
        7Li NMR study of normal human erythrocytes.
        J Magn Reson. 1987; 3–11: 504-519
        • Rybakowski J
        • Frazier A
        • Mendels J
        • Ramsey TA
        Prediction of the lithium ratio in man by means of an in vitro test.
        Clin Pharmacol Ther. 1977; 22: 465-469
        • Shporer M
        • Civan MM
        Nuclear magnetic resonance of sodium-23 linoleate-water. Basis for an alternative interpretation of sodium-23 spectra within cells.
        Biophys J. 1972; 12: 114-122
        • Thakar JH
        • Lapierre YD
        • Waters BG
        Erythrocyte membrane sodium-potassium and magnesium ATPase in primary affective disorders.
        Biol Psychiatry. 1985; 20: 734-740
        • Werstiuk ES
        • Rathbone MP
        • Grof P
        Erythrocyte lithium transport in bipolar affective disorders. The effect of membrane transport inhibitors.
        Neuropsychobiology. 1984; 12: 86-92