Lithium works by interacting with a network of proteins in the brain. Scientists have identified at least 47 proteins in the human body whose activity is influenced by lithium. These lithium-dependent proteins are involved in mood regulation, neurotransmitter balance, and brain cell communication.

The Key Target: Adenylate Cyclase-5

Adenylate cyclase-5 (AC5) is considered the most important for lithium’s mood-stabilizing effects. AC5 is responsible for turning external signals from neurotransmitters into cellular responses.

Neurotransmitters, such as dopamine and adrenaline, bind to the receptors on the surface of brain cells and activate AC5. Lithium blocks AC5 and reduces the response to dopamine and adrenaline. This mechanism dials down overstimulation of the cell, enhances serotonin activity, and supports mood stabilization.

More Lithium-Dependent Proteins

While AC5 plays a central role, several other proteins also contribute to lithium’s effects:

• TPH2 (Tryptophan Hydroxylase 2)
  Lithium interacts with TPH2 and boosts serotonin production from tryptophan.
  

• PTK2B (Tyrosine Kinase 2-beta)
  This protein regulates NMDA receptors, which are involved in memory and learning. Overactive NMDA receptor activity leads to mood instability and stress responses. Lithium blocks PTK2B and reduces excessive NMDA activity.

• GRIA1, GRIA3 (Glutamate Receptors)
  These receptors respond to glutamate, the main excitatory neurotransmitter in the brain. Lithium reduces their expression, which may calm overactive brain circuits involved in anxiety and mania.

• SLC38A1 (Amino Acid Transporter 1)
  This transporter supplies neurons with glutamine, needed to produce both glutamate, a stimulating neurotransmitter, and GABA, a calming neurotransmitter. Lithium inhibits SLC38A1, potentially rebalancing excitatory and inhibitory signals in the brain.
  

• SLC8B1 (Mitochondrial Na/K/Ca Exchanger)
  This protein helps move calcium into mitochondria, which protects brain cells from overactivation and damage. Lithium enhances this protective transport, lowering the risk of cell death due to overstimulation.
  

• ASIC1 (Acid-Sensitive Ion Channel 1)
  Found in nerve cells, this receptor responds to changes in acidity and helps regulate brain network activity. It also helps transport lithium ions, contributing to lithium’s entry into brain cells.

The Bigger Picture

Taken together, these proteins interact with lithium and support healthy emotional regulation.