B.Sc. with First Class Honors, 1979, Imperial College, University of London, UK
Ph.D., 1984, University of California, Los Angeles
Lithium salts are used in the treatment of bipolar disorder but the mechanism of action is poorly understood. We focus on two Mg2+-dependent protein systems, G-proteins and GSK-3β, which are key components of signal transduction pathways believed to malfunction in this mental illness. Our approach incorporates a battery of biophysical methods, including fluorescence and circular dichroism spectroscopy, isothermal titration calorimetry, and nuclear magnetic resonance and electron paramagnetic resonance. Using this methodology, we probe the Li+ and Mg2+ binding and competition properties, and the folding of these proteins.
Mota de Freitas, D.; Leverson, B.D.; Goossens, J.L.: Lithium in Medicine: Mechanism of Action. In The Alkali Metal Ions: Their Role in Life; Metal Ions in Life Sciences, vol. 16; Sigel, A.; Sigel, H.; Sigel, R.K.O.; Eds. Springer International Publishing, Switzerland, 2016, pp. 557-584
Najor, M.S., Olsen, K.W., Graham, D.J., and Mota de Freitas: Contribution of each Trp Residue toward the Intrinsic Fluorescence of the Giα1 Protein. Protein Sci. 2014, 23, 1392-1402.
Malarkey, C.S., Wang, W., Ballicora, M.A., and Mota de Freitas, D.: Evidence for Two Distinct Mg2+ Binding Sites in Gsα and Giα1 Proteins. Biochem. Biophys. Res. Commun. 2008, 372, 866-869.
Mota de Freitas, D., Castro, M.M.C.A., and Geraldes, C.F.G.C.: Is Competition Between Li+ and Mg2+ the Underlying Theme in the Proposed Mechanisms for the Pharmacological Action of Lithium Salts in Bipolar Disorder? Acc. Chem. Res. 2006, 39, 283-291
Layden. B.T., Abukhdeir, A.M., Malarkey, C.M., Oriti, L.A., Salah, W., Stigler, C., Geraldes, G.F.G.C., and Mota de Freitas, D.: Identification of Li+ Binding Sites and the Effect of Li+ Treatment on Phospholipid Composition in Human Neuroblastoma Cells: A 7Li and 31P NMR Study. Biochim. Biophys. Acta 2005, 1741, 339-349.
Montezinho, L.P., Duarte, C.B., Fonseca, C.P., Glinka, Y., Layden, B., Mota de Freitas, D., Geraldes, C.F.G.C., and Castro, M.M.C.A.: Intracellular Lithium and Cyclic AMP Levels are Mutually Regulated in Neuronal Cells. J. Neurochem. 2004, 90, 920-930.
Srinivasan, C., Toon, J., Amari, L., Abukhdeir, A.M., Hamm, H., Geraldes, C.F.G.C., Ho, Y., and Mota de Freitas, D.: Competition between Lithium and Magnesium Ions for the G-protein Transducing in the Guanosine 5'-Diphosphate Bound Conformation. J. Inorg. Biochem . 2004, 98, 691-701.
Layden, B.T., Minadeo, N., Suhy, J., Abukhdeir, A.M., Metreger, T., Foley, K., Borge, G., Crayton, J.W., Bryant, F.B., and Mota de Freitas, D.: Biochemical and psychiatric predictors of Li+ response and toxicity in Li+-treated bipolar patients. Bipolar Disord. 2004, 6, 53-61.
Layden B.T., Abukhdeir A.M., Williams N., Fonseca C.P., Carroll L., Castro M.M.C.A., Geraldes C.F.G.C., Bryant F.B., Mota de Freitas D.: Effects of Li+ transport and Li+ immobilization on Li+ / Mg2+ competition in cells: Implications for bipolar disorder. Biochem. Pharmacol. 2003, 66, 1915-1924.
Minadeo, N., Layden, B.T., Suhy, J., Metreger, T., Foley, K., Abukhdeir, A.M., Borge, G., Crayton, J., Bryant, F.B., and Mota de Freitas, D.: Testing Competing Path Models Linking the Biochemical Variables in Red Blood Cells from Li+-Treated Bipolar Patients Bipolar Disord. 2003, 5, 320-329.
Abukhdeir, A.M.; Layden, B.T.; Minadeo, N.; Bryant, F.B.; Stubbs, Jr., E.B.; Mota de Freitas, D.: Effect of Chronic Li+ Treatment on Free Intracellular Mg2+ in Human Neuroblastoma SH-SY5Y Cells. Bipolar Disord., 2003, 5, 6-13.