Competition between lithium and magnesium ions for the G-protein transducin in the guanosine 5'-diphosphate bound conformation.

Srinivasan C, Toon J, Amari L, Abukhdeir AM, Hamm H, Geraldes CF, Ho YK, Mota de Freitas D
J Inorg Biochem. 2004 98 (5): 691-701

PMID: 15134914 · DOI:10.1016/j.jinorgbio.2003.12.023

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.

MeSH Terms (16)

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

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