Lithium: the pharmacodynamic actions of the amazing ion

Abstract

Lithium has been used for the treatment of mood disorders for over 60 years, yet the exact mechanisms by which it exerts its therapeutic effects remain unclear. Two enzymatic chains or pathways emerge as targets for lithium: inositol monophosphatase within the phosphatidylinositol signalling pathway and the protein kinase glycogen synthase kinase 3. Lithium inhibits these enzymes through displacing the normal cofactor magnesium, a vital regulator of numerous signalling pathways. Here we provide an overview of evidence, supporting a role for the inhibition of glycogen synthase kinase 3 and inositol monophosphatase in the pharmacodynamic actions of lithium. We also explore how inhibition of these enzymes by lithium can lead to downstream effects of clinical relevance, both for mood disorders and neurodegenerative diseases. Establishing a better understanding of lithium's mechanisms of action may allow the development of more effective and more tolerable pharmacological agents for the treatment of a range of mental illnesses, and provide clearer insight into the pathophysiology of such disorders.

Keywords: glycogen synthase kinase 3; inositol monophosphatase; lithium; pharmacology.

Figure 1.

Inositol depletion within the PI signalling pathway. An agonist binds to a receptor complex, consisting of a receptor, Gq-protein and phospholipase (PLC). PLC hydrolyses the phospholipid phosphatidylinositol 4,5-biophosphate (PIP₂) to form two second messengers: inositol-1,4,5 triphosphate (IP₃) and 1,2-diacylglycerol (DAG). IP3 binds to specific receptors to help open the calcium (Ca²⁺) channel and DAG initiates activation of protein kinase C (PKC). IP3 is sequentially broken down into inositol bisphosphates (IP₂) and then inositol monophosphates (IP). IP is finally broken down into myo-inositol by the enzyme inositol monophosphatase (IMPase). Lithium inhibits IMPase, leading to myo-inositol depletion. Myo-inositol is also the substrate for synthesis of phosphatidylinositol (PI), which is phosphorylated to form mono-, bis- and tris- phosphatidylinositol. Lithium induced myo-inositol depletion therefore prevents the resynthesis of PIP2 and subsequent regeneration of IP3 and DAG, affecting cell signalling.

Figure 2.

Inhibition of glycogen synthase kinase 3 (GSK3) by lithium. Lithium directly inhibits GSK3 by competitive binding for magnesium (Mg²⁺), disrupting the catalytic functioning of GSK3. Lithium also indirectly inhibits GSK3 by increasing serine phosphorylation, through P13K-mediated phosphorylation/activation of Akt. Lithium is able to activate Akt by disrupting the formation of a protein kinase B (Akt), beta-arrestin 2(βArr2) and protein phosphatase 2A (Akt;βArr2;PP2A) comprised signalling complex, triggered by activation of the dopamine 2 receptor (D2R) and potentially other G-protein coupled receptors (GPCR). The Akt;βArr2;PP2A signalling complex typically leads to inactivation of Akt, preventing GSK3 inhibition; the destabilisation of this signalling complex by lithium reduces Akt dephosphorylation, enhancing Akt activity, thus indirectly inhibiting GSK3.