EF-hands in Neuronal Calcium Sensor Downstream Regulatory Element Antagonist Modulator Demonstrate Submillimolar Affinity for Li+: A New Prospect for Li+ Therapy

Lithium has been used for the treatment of mood disorders for decades though the molecular mechanism of its therapeutic action and intracellular targets remain furtive. We report that neurotropic agent Li+ binds to the neuronal calcium sensor, Downstream Regulatory Element Antagonist Modulator (DREAM), with an equilibrium dissociation constant of 34 +/- 4 mu M and impacts DREAM structural and dynamic properties in a similar manner as observed for its physiological ligand, Ca2+. Results of fluorescence spectroscopy and molecular dynamics are consistent with Li+ binding at EF-hands. In the Li+ bound form, DREAM association to peptides mimicking DREAM binding sites in a voltage-gated potassium channel is enhanced compared to the apoprotein, whereas DREAM affinity for the presenilin binding site, helix-9, is impeded. These results suggest that DREAM and possibly other members of the neuronal calcium sensor family belong to Li+ intracellular targets and interactions between Li+ and NCS provide a molecular basis for Li+ neuroprotective action.