Lithium Leads to an Increased FRQ Protein Stability and to a Partial Loss of Temperature Compensation in the Neurospora Circadian Clock

Abstract

In many organisms, the presence of lithium leads to an increase of the circadian period length. In Neurospora crassa, it was earlier found that lithium results in a decrease of overall growth and increased circadian periods. In this article, the authors show that lithium leads to a reduction of FRQ degradation with elevated FRQ levels and to a partial loss of temperature compensation. At a concentration of 13 mM lithium, FRQ degradation is reduced by about 60% while, surprisingly, the activity of the 20S proteasome remains unaffected. Experiments and model calculations have shown that the stability of FRQ is dependent on its phosphorylation state and that increased FRQ protein stabilities lead to increased circadian periods, consistent with the observed increase of the period when lithium is present. Because in Neurospora the proteasome activity is unaffected by lithium concentrations that lead to significant FRQ stabilization, it appears that lithium acts as an inhibitor of kinases that affect phosphorylation of FRQ and other proteins. A competition between Li(+) and Mg(2+) ions for Mg(2+)-binding sites may be a mechanism to how certain kinases are inhibited by Li(+). A possible kinase in this respect is GSK-3, which in other organisms is known to be inhibited by lithium. The partial loss of temperature compensation in the presence of lithium can be understood as an increase in the overall activation energy of FRQ degradation. This increase in activation energy may be related to a reduction in FRQ phosphorylation so that more kinase activity, that is, higher temperature and longer times, is required to achieve the necessary amount of FRQ phosphorylation leading to turnover. Using a modified Goodwin oscillator as a semiquantitative model for the Neurospora clock, the effects of lithium can be described by adding lithium inhibitory terms of FRQ degradation to the model.

Glycogen Synthase Kinase Is a Regulator of the Circadian Clock of Neurospora crassa

“…In contrast, lithium, which is known to inhibit GSK activity, was reported to have a period lengthening effect in mammals (24,37). These observations are comparable to the ones made in Neurospora, where lithium causes severe period lengthening (38), while down-regulation of GSK led to significant period shortening. Inhibition of GSK could have a different effect than down-regulation of the kinase.…”

Influence of Lithium ions on conidiophore size in Neurospora crassa

“…Typically, at extracellular concentrations of 10 mM LiCl, the growth rate is significantly reduced and the circadian clock begins to get disrupted (Engelmann 1987;Lakin-Thomas 1993;Jolma et al 2006). Interestingly, increased temperature can abolish the Li effect, possibly by an increased dissociation between Li and its assumed targets (Jolma et al 2006). Because of the macroscopically distinct differences in conidiation when Neurospora is grown in the presence or absence of Li, we wondered whether there might be also a difference in microscopic conidiation, for example conidia size.…”

“…Lithium (Li) has a profound influence on Neurospora crassa's growth rate and circadian period (Engelmann 1987;Davis 2000;Dunlap and Loros 2004). Typically, at extracellular concentrations of 10 mM LiCl, the growth rate is significantly reduced and the circadian clock begins to get disrupted (Engelmann 1987;Lakin-Thomas 1993;Jolma et al 2006). Interestingly, increased temperature can abolish the Li effect, possibly by an increased dissociation between Li and its assumed targets (Jolma et al 2006).…”

“…In order to answer this question, we performed a study using a Zeiss Supra VP35 scanning electron microscope (SEM) with a Polaron cryo stage. The bd a strain (FGSC #1859) was grown on Petri dishes in LD (12h:12h) at 20°C or 30°C using Vogel's medium as previously described (Jolma et al 2006). Li was added to the medium as LiCl.…”

Estudo de associação entre disfunção neurocognitiva, estresse oxidativa e polimorfismos em pacientes jovens com Transtornos Bipolar tipo I

“…Patients with BD often demonstrate circadian disturbances, and lithium has been shown to increase circadian period in humans and animals (92,102,103), consistent with a consistent decrease in GSK-3 activity. Studies showing that psychomimetic drugs (amphetamine, Lysergic acid diethylamide (LSD), and Phencyclidine (PCP)) increase GSK-3 phosphorylation in frontal cortex and striatum (104) provide circumstantial support for the possibility of an underlying GSK-3 abnormality in BD.…”