guanosine-triphosphate and Bipolar-Disorder

Li(+) is the most effective drug used to treat bipolar disorder; however, its exact mechanism of action has yet to be elucidated. One hypothesis is that Li(+) competes with Mg2+ for the Mg2+ binding sites on guanine-nucleotide binding proteins (G-proteins). Using 7Li T1 relaxation measurements and fluorescence spectroscopy with the Mg2+ fluorophore furaptra, we detected Li(+)/Mg(2+) competition in three preparations: the purified G-protein transducin (Gt), stripped rod outer segment membranes (SROS), and SROS with purified Gt reattached (ROS-T). When purified ROS-T, SROS or transducin were titrated with Li+ in the presence of fixed amounts of Mg(2+), the apparent Li(+) binding constant decreased due to Li(+)/Mg(2+) competition. Whereas for SROS the competition mechanism was monophasic, for G(t), the competition was biphasic, suggesting that in G(t), Li(+)/Mg(2+) competition occurred with different affinities for Mg(2+) in two types of Mg(2+) binding sites. Moreover, as [Li(+)] increased, the fluorescence excitation spectra of both ROS-T and G(t) were blue shifted, indicating an increase in free [Mg(2+)] compatible with Li(+) displacement of Mg(2+) from two low affinity Mg(2+) binding sites of G(t). G(t) release from ROS-T membrane was also inhibited by Li(+) addition. In summary, we found evidence of Li(+)/Mg(2+) competition in G(t)-containing preparations.

Topics: Animals; Binding, Competitive; Bipolar Disorder; Cattle; Guanosine Diphosphate; Guanosine Triphosphate; Humans; In Vitro Techniques; Kinetics; Lithium; Magnesium; Magnetic Resonance Spectroscopy; Protein Conformation; Rod Cell Outer Segment; Spectrometry, Fluorescence; Transducin

Guanine nucleotide binding proteins (G proteins) have been implicated in the pathophysiology of bipolar affective disorder. In the present investigation receptor-mediated G protein activation and changes in G protein trimeric state were examined in frontal cortical membranes obtained from postmortem brains of bipolar affective disorder subjects and from age-, sex-, and postmortem interval-matched controls. Stimulation of cortical membranes with serotonin, isoproterenol, or carbachol increased guanosine 5'-O-(3-[35S]thiophosphate) ([35S]GTP gamma S) binding to specific G alpha proteins in a receptor-selective manner. The abilities of these receptor agonists to stimulate the binding of [35S]GTP gamma S to the G alpha proteins was enhanced in membranes from bipolar brains. Immunoblot analyses showed increases in the levels of membrane 45- and 52-kDa G alpha S proteins but no changes in the amounts of G alpha i, G alpha o, G alpha Z, G alpha q/11, or G beta proteins in membrane or cytosol fractions of bipolar brain homogenates. Pertussis toxin (PTX)-activated ADP-ribosylations of G alpha i and G alpha o were enhanced by approximately 80% in membranes from bipolar compared with control brains, suggesting an increase in the levels of the trimeric state of these G proteins in bipolar disorder. Serotonin-induced, magnesium-dependent reduction in PTX-mediated ADP-ribosylation of G alpha i/G alpha o in cortical membranes from bipolar brains was greater than that observed in controls, providing further evidence for enhanced receptor-G protein coupling in bipolar brain membranes. In addition, the amounts of G beta proteins that coimmunoprecipitated with the G alpha proteins were also elevated in bipolar brains. The data show that in bipolar brain membrane there is enhanced receptor-G protein coupling and an increase in the trimeric state of the G proteins. These changes may contribute to produce exaggerated transmembrane signaling and to the alterations in affect that characterize bipolar affective disorder.

Topics: Adenylyl Cyclases; Aged; Aged, 80 and over; Autopsy; Autoradiography; Bipolar Disorder; Brain Chemistry; Female; Frontal Lobe; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Humans; Immunoblotting; Male; Membrane Proteins; Middle Aged; Phosphorus Radioisotopes; Precipitin Tests; Receptors, Cell Surface; Receptors, Serotonin; Serotonin Receptor Agonists; Sulfur Radioisotopes

1. The study was done to determine whether long-term treatment with lithium carbonate affected the guanosine triphosphate (GTP)-binding protein in platelet membranes from patients with manic depression. 2. It was found that adenosine diphosphate (ADP)-ribosylation of inhibitory G-proteins (40-41 kDa) by pertussis toxin, islet-activating protein in the cell membranes increased about 45% when long-term treatment with lithium carbonate was stopped. 3. These results support the idea that one site for the therapeutic effects of lithium ions is G-proteins.

Topics: Adenosine Diphosphate; Bipolar Disorder; Blood Platelets; GTP-Binding Proteins; Guanosine Triphosphate; Humans; Lithium; Lithium Carbonate; Pertussis Toxin; Protein Binding; Time Factors; Virulence Factors, Bordetella

Lithium is a unique drug with therapeutic as well as prophylactic value for both manic and depressive phases of manic-depressive illness. The precise mechanisms of its clinical efficacy remain unknown, but there are two main theories of its biochemical action. One proposes that lithium inhibits adrenergically activated adenylate cyclase function whereas the other suggests that it inhibits phosphatidyl inositol turnover, which is known to be activated by cholinergic agonists. Neither mechanism alone, however, can explain both the antimanic and antidepressant effects of lithium. Because of the pivotal role of G proteins in post-receptor information transduction, we have investigated the interaction of lithium with G protein function. Lithium at therapeutically efficacious concentrations completely blocked both adrenergic and cholinergic agonist-induced increases in [3H]GTP binding to membranes from rat cerebral cortex, in both in vitro and ex vivo experiments. The same lithium treatments also abolished guanine nucleotide modulation of agonist binding. Our findings suggest G proteins (Gs and Gi or Go) as the molecular site of action for both the antimanic and antidepressant effects of lithium.

Topics: Animals; Atropine; Bipolar Disorder; Carbachol; Cerebral Cortex; Guanosine Triphosphate; Isoproterenol; Lithium; Male; Propranolol; Rats