Fluorescence and NMR Studies on the Competition Between Lithium and Magnesium Ions for Native and Mutated Gialpha1 Proteins

Lithium salts (Li+) are used to treat bipolar disorder. One hypothesis for the pharmacological mechanism of Li+ is that Li+ competes with the magnesium ion (Mg2+) for Mg2+ binding sites in guanine nucleotide binding proteins (G proteins) and deactivates them. G proteins (composed of alpha, beta, and gamma subunits) serve as transducers between receptors and effectors in signaling pathways in cells. The function of G protein is regulated by the exchange of GDP by GTP on the alpha subunit (activation) and the hydrolysis of GTP to GDP (deactivation). GTP binding changes the conformation in three regions (switch I, switch II, switch III) in the a subunit, and Mg 2+ plays a vital role in both the activation and deactivation steps. In this dissertation, the role of Mg2+ in the function of G ialpha1 protein (the alpha subunit of the Gi1 protein which inhibits adenylate cyclase) and the competition between Li+ and Mg2+ for Mg2+ binding sites in G ialpha1 proteins were studied using fluorescence and nuclear magnetic resonance (NMR) spectroscopy.