| Li+ is the primary drug to treat bipolar disorder, however, its exact mechanism of action is unknown. Guanine nucleotide-binding (G) proteins are involved in signal transduction, and therefore, much effort has been given to elucidate their role in bipolar disorder. Because these proteins are Mg 2+ dependent, the Li+/Mg2+ competition hypothesis with respect to binding and activation was explored with a G-protein, rGialpha1, and two of its mutants (T181D and T181V). Using fluorescence spectroscopy and 7Li NMR relaxation rates, we found that ion competition did occur in the three forms of rGialpha1, as well as significantly decreased Mg2+ binding and activation in one of the mutant forms, T181V.;Although Li+ decreases the number of episodes associated with bipolar disorder, some patients do not respond to treatment, while others become toxic. Therefore, it would be valuable to determine whether the patient will respond or become toxic to Li+ prior to treatment. Through 7Li and 31P NMR spectroscopy, and AA (atomic absorption) spectrophotometry, we determined Li+ transport and binding values, phospholipid composition, and intracellular [Mg2+] f in red blood cells (RBCs) from 30 Li+-treated bipolar patients and found that at least one of these biochemical variables has a strong predictive value in determining response and toxicity.;The cytoskeleton is a feature of the RBC that supports the cytoplasmic face. To determine whether the loss of the cytoskeleton enhances ion binding and competition for membrane binding sites, we used unsealed and cytoskeleton-depleted RBC membrane samples in conjunction with 7Li NMR relaxation rates. We observed an increase in Li+ binding and ion competition in cytoskeleton-depleted membrane samples, which indicates that phospholipid head groups as well as membrane proteins contribute toward Li+ binding in the RBC membrane.;G-proteins regulate ion transport, and may provide insight into hypertension. Abnormal function of certain G-proteins may be the cause of irregularities in Na+ transport, which is often seen with this disease. By fluorescence and 23Na+ NMR spectroscopy, we found that Na+ readily competes for Mg2+-binding sites in rGialpha1 and affects the activity of the protein. These findings support the theory that in hypertensive patients the functioning of G-proteins is altered. Hypertensive patients also display alterations in intracellular [Mg2+]f levels when compared to normotensives. Upon treatment with antihypertensive medication, these levels were similar to normotensives. Intracellular [Mg2+]f, phospholipid composition, and Na+ transport and binding in RBCs from 15 treated and 4 untreated essential hypertensives were studied using 23Na+ and 31P NMR spectroscopy, and AA spectrophotometry. This study sought to determine if treatment with antihypertensive medication would correct alterations in these biochemical parameters. No definitive conclusions can be drawn from the hypertension study because of the difficulty in obtaining blood samples from untreated hypertensives, and thus the resulting small sample size. |
