Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology

Jakobsson, Eric; Argüello-Miranda, Orlando; Chiu, See‐Wing; Fazal, Zeeshan; Kruczek, James; Núñez-Corrales, Santiago; Pandit, Sagar A.; Pritchet, Laura

doi:10.1007/s00232-017-9998-2

Cited by 120 publications

(103 citation statements)

References 202 publications

(165 reference statements)

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“…Rather it shares pathways that are mainly selective for other ions, in most cases sodium. 2 Therefore, lithium concentration in both extracellular and intracellular compartments, rather than being nearly constant as is the case with other ions, is roughly proportional to lithium ingestion. 54 Whereas changes in the concentrations of other ions of more than a few percent have severe acute adverse consequences, the human body adjusts without acute adverse consequence to changes in lithium concentrations of several orders of magnitude.…”

Section: Summary and Discussionmentioning

confidence: 99%

“…Much of lithium's known biochemical action may be summarized by noting that it inhibits some phosphate-transfer enzymes (primarily phosphatases and kinases) that have magnesium as a co-factor. 2 A common underlying biophysical basis for competition between lithium and magnesium for modulating phosphate-transfer enzymes, is suggested by noting that the primary energy source for cells and the substrate for phosphorylating enzymes is not bare ATP, but rather magnesium-associated ATP (MgATP). 24 NMR studies show that lithium associates with MgATP.…”

Section: Biochemical Context For Lithium and Cancermentioning

confidence: 99%

“…1 A comprehensive review of the literature 26 confirms that lithium is also effective against unipolar depression with unique anti- 27 suicidal effectiveness, and may also be useful against cancer and neurodegenerative 28 disease. 2 29 One line of evidence for the possible use of lithium as an anticancer agent is 30 epidemiological. A retrospective study showed that psychiatric patients undergoing 31 lithium therapy for bipolar disorder had a much lower incidence of cancer than a matched 32 group not receiving lithium therapy.…”

Section: Introduction 23mentioning

confidence: 99%

“…The full range of lithium effects on autophagy is complicated, 23 as might be expected 71 because of lithium's lack of specificity. 2…”

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confidence: 99%

“…24 75 76 Biochemical Context for Lithium and Cancer: Much of lithium's biochemical action 77 may be summarized by noting that it inhibits, or competes with, action of 78 magnesium. 2 Examples of such competition, that appear specially relevant for cancer, 79 are given below. 80 Lithium appears to inhibit β-adrenergic and muscarinic receptor coupling to G 81 proteins by competing with magnesium, which facilitates such coupling.…”

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confidence: 99%

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Systems Biology Understanding of the Effects of Lithium on Cancer

Jakobsson

2018

Preprint

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10 Lithium has many widely varying biochemical and phenomenological effects, suggesting 11 that a systems biology approach is required to understand its action. Multiple lines of 12 evidence point to lithium as a significant factor in development of cancer, showing that 13 understanding lithium action is of high importance. In this paper we undertake first steps 14 towards a systems approach by analyzing mutual enrichment between the interactomes of 15 lithium-sensitive enzymes and the pathways associated with cancer. This work integrates 16 information from two important databases, STRING and KEGG pathways. We find that 17for the majority of cancer pathways the mutual enrichment is many times greater than 18 chance, reinforcing previous lines of evidence that lithium is an important influence on 19 cancer.

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Section: Summary and Discussionmentioning

confidence: 99%

Section: Biochemical Context For Lithium and Cancermentioning

confidence: 99%

Section: Introduction 23mentioning

confidence: 99%

“…The full range of lithium effects on autophagy is complicated, 23 as might be expected 71 because of lithium's lack of specificity. 2…”

mentioning

confidence: 99%

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confidence: 99%

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Systems Biology Understanding of the Effects of Lithium on Cancer

Jakobsson

2018

Preprint

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Markedly Different Effects of Monovalent Cations on the Efficiency of Gene Expression

et al. 2022

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optimal concentrations of the monovalent cations were ≈80 mm and had maxima with respect to TL efficiencies in the order K + > Rb + > Cs + > Na + ≈ Li + . Regarding the binding/association affinity of monovalent cations for DNA, several studies have reported the order Li + > Cs + > Rb + > K + ≈ Na +[9-11] or a similar ordering, [12,13] although the differences in affinity among the monovalent cations are not significant and depend on the experimental methods used. In contrast, an exactly reverse order of action for the binding affinity of the progesterone receptor to DNA binding was reported, and such reverse order was attributed to the competitive effect of monovalent cations in the receptor-DNA interaction. [14] Except for the unique behavior of Li + , this ordering of the binding potential has been explained, [15,16] as monovalent ions with a smaller size of hydration, corresponding to a larger ionic radius, [17][18][19] may cause a larger Coulombic attractive interaction with negatively charged DNA. On the contrary, it was reported that stronger counter ion condensation, [20] as well as larger contraction of DNA minor groove, [21] is induced by monovalent cation with smaller size; Li + > Na + > K + > Rb + . As a different proposal, Gebala et al. argued [22] that ion atmosphere occupancy around double-strand DNA is insensitive to the cation size across the alkali metal ions Na + , K + , Rb + , Cs + , except for a preference of around 25% for Li + . Based on the hypothesis of counterion condensation, a number of studies have reported the specific manner of interaction of cationic counterions with DNA molecules as highly negative-charged polyelectrolytes, including the effect on higher-order structural changes. [23][24][25] Concerning polymer-and-salt-induced condensation of DNA (Ψ-condensation), Zinchenko et al. [26] performed measurements of single DNA molecules for the transition of higher-order structure from an elongated coil into a compact globule. The observation on the conformational transition was carried out on individual genomesized DNA molecules (T4 GT7 DNA) in a crowded environment with polyethylene glycol, and the researchers found that monovalent ions promote the folding transition with the potentiality:

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Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

Lee

Zhang

Park

et al. 2020

Annals of Neurology

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Objective Genetic variants of the cytoplasmic FMR1‐interacting protein 2 (CYFIP2) encoding an actin‐regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2‐associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/−) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/− mice and specified a neuronal function mediating its efficacy. Methods We performed behavioral analyses of Cyfip2+/− mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/− prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. Results Adult Cyfip2+/− mice exhibited lithium‐responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/− PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/− mice showed increased seizure susceptibility and auditory steady‐state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/− L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/− PFC. Virus‐mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium‐responsive abnormal behavior. Interpretation These results suggest that L5‐specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium‐mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/− mice, which can be implicated in CYFIP2‐associated brain disorders. ANN NEUROL 2020;88:526–543

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Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology

Cited by 120 publications

References 202 publications

Systems Biology Understanding of the Effects of Lithium on Cancer

Systems Biology Understanding of the Effects of Lithium on Cancer

Markedly Different Effects of Monovalent Cations on the Efficiency of Gene Expression

Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

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