Interactions of Li ions with NCS1: A potential mechanism of Li neuroprotective action against psychotic disorders.

Li based drugs have been used for the treatment of psychiatric disorders due to their mood stabilizing role for decades. Recently, several studies reported the protective effect of Li against severe neuropathologies such as Parkinson's, Alzheimer's, and Huntington's disease. Surprisingly, despite a broad range of Li effects on neurological conditions, little is known about its molecular mechanism. In this study, we propose that neuronal calcium sensor 1 (NCS1), can be an effective molecular target for Li action. Here we show that the EF-hands in ApoNCS1 have submillimolar affinity for Li with K = 223 ± 19 μM. Li binding to ApoNCS1 quenches Trp emission intensity, suggesting distinct Trp sidechains environment in LiNCS1 compared to ApoNCS1 and CaNCS1. Li association also stabilizes the protein α-helical structure, in a similar way to Ca. Li association does not promote NCS1 dimerization. Association of Li increases NCS1 affinity for the D2R receptor binding peptide, in a similar way to Ca, however, the affinity of NCS1 for chlorpromazine is reduced with respect to CaNCS1, possibly due to a decrease in solvent exposed hydrophobic area on the NCS1 surface in the presence of Li. MD simulation data suggests that Li ions are coordinated by four oxygens from Asp and Glu sidechains and one carbonyl oxygen, in a similar way as reported previously for Li binding to DREAM. Overall, the data shows that Li binds to EF-hands of NCS1 and LiNCS1 interactions may be involved in the potential neuroprotective role of Li against psychotic disorders.