Free and Bound Therapeutic Lithium in Brain Signaling
Lithium has remained the first-line therapy for bipolar disorder for ~50 years, yet the exact molecular mechanism of its therapeutic action remains unclear. The existing biological hypotheses are based largely on lithium acting as a free cation. We propose that lithium’s multifaceted activities can be explained by considering its interactions as a free monocation competing with native cations in proteins as well as as a phosphate-bound polyanionic complex modulating the host protein function.
Lithium ion (Li+), a first-line therapy for bipolar disorder, is effective in preventing suicide and new depressive/manic episodes. Recently, it is also considered for treating traumatic brain injury and various neurodegenerative conditions including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Lithium’s therapeutic action is highly complex, inducing multiple effects on gene expression, neurotransmitter/receptor-mediated signaling, circadian regulation, and ion transport. Yet, how this beguilingly simple monocation with only two electrons could yield such profound therapeutic effects remains unclear. Various proposed modes of lithium’s therapeutic action suggest that lithium’s effects are mostly related to its interactions with native cations, especially Na+ and Mg2+, in various signaling proteins and organic cofactors.
We addressed the following aspects of lithium’s therapeutic actions:
- 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?
- Why are certain Mg2+-dependent enzymes targeted by Li+?
- 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?
- How do NTP-Mg-Li complexes modulate the properties of the respective cellular receptors and signal-transducing proteins?
- 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.
- Li+ 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.
- Li+ binding to Mg2+-NTP in water alters neither the NTP conformation, which is locked by all three phosphates binding to Mg2+, nor the native cofactor’s net charge as the water molecule bridging Li+ to Mg2+ is deprotonated.
- 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 terminal two 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, as observed experimentally. 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.
Unlike drugs that exist in one form and act on a specific target, lithium exists in both free and bound forms and acts on multiple targets. We propose a unifying physicochemical basis that underlies lithium’s multifaceted effects by considering its interactions as a free monocation with native cations or as a phosphate-bound polyanionic complex modulating the host protein function. An in-depth understanding of lithium’s mechanisms of actions would help to develop better treatments limiting its adverse side effects and to repurpose lithium for treating other diseases such as traumatic brain injury and chronic neurodegenerative.