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

Abstract

Li+ based drugs have been used for treatment of psychiatric disorders due to their mode stabilizing role for decades. Recently, several studies reported 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, relatively little is known about its molecular mechanism and so far only two molecular targets, inositol monophosphatase (IMPase) and glycogen synthase kinase-3-beta (GSK-3β) have been described in the literature. Here we propose that neuronal calcium sensor 1 (NCS1), can be an effective molecular target of Li+ action. NCS1 is a 23-kDa protein that contains highly conserved 190 amino acid residues. NCS1 participates in a wide number of cellular functions such as exocytosis, neurite outgrowth and neuroprotection through interactions with numerous intracellular proteins including AFR1, CaV2.1, D2R, InsP3R. NCS1 was implicated in several neuronal diseases including bipolar disorder, schizophrenia, Parkinson's disease etc. Here we show that the EF-hands in NCS1 have relatively high affinity for Li+ and Li+ binding impacts NCS1 structural and functional properties. Namely, fluorescence titration data show that Li+ binds to the apoNCS1 with the equilibrium dissociation constant of 223.3±5.0 µM. Li+ association to NCS1 increases its affinity for the hydrophobic organic molecule 1,8-ANS and triggers an increase in the α-helical structure of the protein. Li+ promotes the NCS1 binding to D2R peptide and the antipsychotic medication chlorpromazine as well. MD studies show that Li+ associates to EF hands 2 to 3 and is coordinated through oxygen atoms from the acidic amino acid residues. Overall data show that Li+ acts as a potential target for binding to the EF-hands of NCS1 and plays a potential neuroprotective role against the psychotic disorders.