Lithium, a first-line therapy for bipolar disorder, is effective in preventing suicide and new depressive/manic episodes. Yet, how this beguilingly simple monocation with only two electrons could yield such profound therapeutic effects remains unclear. An in-depth understanding of lithium’s mechanisms of actions would help one to develop better treatments limiting its adverse side effects and repurpose lithium for treating traumatic brain injury and chronic neurodegenerative diseases.

In this Account, we begin with a comparison of the physicochemical properties of Li⁺ and its key native rivals, Na⁺ and Mg²⁺, to provide physical grounds for their competition in protein binding sites. Next, we review the abnormal signaling pathways and proteins found in bipolar patients, who generally have abnormally high intracellular Na⁺ and Ca²⁺ concentrations, high G-protein levels, and hyperactive phosphatidylinositol signaling and glycogen synthase kinase-3β (GSK3β) activity. We briefly summarize experimental findings on how lithium, at therapeutic doses, modulates these abnormal signaling pathways and proteins. Following this survey, we address the following aspects of lithium’s therapeutic actions: (1) Can Li⁺ displace Na⁺ from the allosteric Na⁺-binding sites in neurotransmitter transporters and G-protein coupled receptors (GPCRs); if so, how would this affect the host protein’s function? (2) Why are certain Mg²⁺-dependent enzymes targeted by Li⁺? (3) How does Li⁺ binding to Mg²⁺-bound ATP/GTP (denoted as NTP) in solution affect the cofactor’s conformation and subsequent recognition by the host protein? (4) How do NTP–Mg–Li complexes modulate the properties of the respective cellular receptors and signal-transducing proteins?

We show that Li⁺ may displace Na⁺ from allosteric Na⁺-binding sites in certain GPCRs and stabilize inactive conformations, preventing these receptors from relaying signal to the respective G-proteins. It may also displace Mg²⁺ in enzymes containing highly cationic Mg²⁺-binding sites such as GSK3β, but not in enzymes containing Mg²⁺-binding sites with low or zero charge.

We further show that Li⁺ binding to Mg²⁺-NTP in water does not alter the NTP conformation, which is locked by all three phosphates binding to Mg²⁺. However, bound lithium in the form of [NTP–Mg–Li]^2–dianions can activate or inhibit the host protein depending on the NTP-binding pocket’s shape, which determines the metal-binding mode: The ATP-binding pocket’s shape in the P2X receptor is complementary to the native ATP–Mg solution conformation and nicely fits [ATP–Mg–Li]^2–. However, since the ATP βγ phosphates bind Li⁺, bimetallic [ATP–Mg–Li]^2– may be more resistant to hydrolysis than the native cofactor, enabling ATP to reside longer in the binding site and elicit a prolonged P2X response. In contrast, the elongated GTP-binding pockets in G-proteins allow only two GTP phosphates to bind Mg²⁺, so the GTP conformation is no longer “triply-locked”. Consequently, Li⁺ binding to GTP-Mg can significantly alter the native cofactor’s structure, lowering the activated G-protein level, thus attenuating hyperactive G-protein-mediated signaling in bipolar patients.

In summary, we have presented a larger “connected” picture of lithium’s diverse effects based on its competition as a free monocation with native cations or as a phosphate-bound polyanionic complex modulating the host protein function.