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

Abstract

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_d = 223 ± 19 μM. Li⁺ binding to ApoNCS1 quenches Trp emission intensity, suggesting distinct Trp sidechains environment in Li⁺NCS1 compared to ApoNCS1 and Ca²⁺NCS1. Li⁺ association also stabilizes the protein α-helical structure, in a similar way to Ca²⁺. Li⁺ association does not promote NCS1 dimerization. Association of Li⁺ increases NCS1 affinity for the D2R receptor binding peptide, in a similar way to Ca²⁺, however, the affinity of NCS1 for chlorpromazine is reduced with respect to Ca²⁺NCS1, 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 Li⁺NCS1 interactions may be involved in the potential neuroprotective role of Li⁺ against psychotic disorders.