Exploration of Lithium Ion Binding to Magnesium Bound Adenosine Triphosphate and Its Implications for Bipolar Disorder

Title of dissertation: EXPLORATION OF LITHIUM ION BINDING TO MAGNESIUM BOUND ADENOSINE TRIPHOSPHATE AND ITS IMPLICATIONS FOR BIPOLAR DISORDER Katharine Therese Briggs, Doctor of Philosophy, 2015 Dissertation directed by: John P. Marino, Ph.D. Department of Chemistry & Biochemistry Lithium carbonate, a drug for the treatment of Bipolar Disorder, provides mood stability to treat an illness that causes recurrent episodes of mania and/or depression. The mechanism by which lithium acts to elicit these psychological changes remains unknown. Interestingly, this small bio-active salt has been shown to reduce the risk of suicide, and appears to lower the incidence of Alzheimer’s disease. It has been proposed that lithium inhibits magnesium-dependent enzymes; however, there is no consensus as to how this occurs. Based on high resolution 7 Li, 23 Na, and 31 P T1 and Paramagnetic Relaxation Enhancement (PRE) Nuclear Magnetic Resonance (NMR) methods, which can be used to characterize the association of lithium (Li + ) at magnesium (Mg 2+ )-phosphorus chelation sites, we have identified a ATP·Mg·Li complex. The lithium binding affinity to form this complex is relatively high compared to other monovalent cations, with a Kd < 1 mM, and biologically relevant considering that at the typical dosing of Li + , physiological concentrations of Mg and ATP are in the 0.6 – 2.5 mM range. This has led us to propose a mechanism of action for lithium based on the formation of Mg·Li-complexes at dehydrated magnesium-phosphate sites and perhaps a role for ATP·Mg as a physiological carrier for Li + . To test this model experimentally in the context of relevant ATP-protein binding sites, we have used NMR methods to characterize the formation of the complex at ATP binding sites on albumin. Similarly, we initiated studies investigating the relevance of the ATP·Mg·Li complex to a class of purinergic receptor proteins (P2XR), since they are stimulated by purine agonists and have been implicated in Bipolar Disorder. EXPLORATION OF LITHIUM ION BINDING TO MAGNESIUM BOUND ADENOSINE TRIPHOSPHATE AND ITS IMPLICATIONS FOR BIPOLAR DISORDER