Further research is now needed, to clarify the clinical relevanc

Further research is now needed, to clarify the clinical relevance of these findings and determine the mood stabilising effects of GSK3 and IMPase inhibition in patients with mood disorders [Beaulieu et al. 2008]. Magnesium: the common cofactor One key hypothesis

for the inhibitory effects of lithium on enzymatic targets such as GSK3 and IMPase postulates the competition between lithium and the Inhibitors,research,lifescience,medical native enzymatic cofactor magnesium for metal-binding sites [Dudev and Lim, 2011]. Lithium and magnesium (group IIA) possess similar ionic radii (0.60 and 0.65 Å, respectively) and similar physicochemical properties [Dudev and Lim, 2011]. As a result, lithium is able to compete with magnesium and successfully bind to metal-binding sites in several magnesium-dependent enzymes including GSK3 [Ryves and Harwood, 2001] and IMPase [Leech et al. 1993; Haimovich et al. 2012]. Lithium also competes with magnesium for Akt/beta-arrestin-2

interaction, thus providing an explanation for lithium’s ability to destabilise the Inhibitors,research,lifescience,medical Akt;βArr2;PP2A signalling complex [Beaulieu et al. 2008]. Although magnesium possesses three binding sites, lithium ions reside in the low-affinity magnesium binding site II and preferentially Inhibitors,research,lifescience,medical bind to solvent-exposed magnesium sites with a positive charge density [Haimovich et al. 2012]. This specificity explains why lithium displaces magnesium only in certain enzymes that are key targets of lithium therapy, not in magnesium Inhibitors,research,lifescience,medical enzymes that are essential to cells [Dudev and Lim, 2011]. The downstream effects of lithium The therapeutic effects of lithium typically require long-term treatment and its beneficial actions are not immediately reversed Inhibitors,research,lifescience,medical following discontinuation of treatment [Chiu and Chuang, 2010]. This has led to the hypothesis that the effects of lithium

on aberrant signalling pathways trigger long-term changes in neuronal intracellular signalling patterns [Lenox and Hahn, 2000], leading to downstream effects of clinical relevance. Accumulating evidence suggests that the therapeutic effects of mood stabilisers are realised through neurotrophic/neuroprotective effects, PFT�� clinical trial offering an explanation for the clinical efficacy of lithium in mood disorders and implicating lithium until as a potential therapeutic agent in the treatment of neurodegenerative diseases [Hunsberger et al. 2009]. Cytoskeletal growth stabilisation and plasticity Lithium alters the level of phosphorylation of cytoskeletal proteins, leading to neuroplastic changes [Lenox and Hahn, 2000]. GSK3 phosphorylates various proteins, including microtubule-associated proteins (MAPs), such as tau and MAP-1B, which regulate the neuronal cytoskeletal network. Inhibition of GSK3 by lithium [Klein and Melton, 1996; Stambolic et al. 1996; Chalecka-Franaszek and Chuang, 1999; De Sarno et al. 2002; Beaulieu et al.

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