Vesicular Monoamine Transporter 2 (VMAT2) is a protein found within the brain that plays a role in brain communication. It packages specific chemical messengers, known as neurotransmitters, into vesicles. This packaging is essential for these messengers to be released and transmit signals between brain cells. Proper VMAT2 function is important for maintaining healthy brain activity.
What VMAT2 Does
VMAT2 transports monoamine neurotransmitters, including dopamine, norepinephrine, serotonin, and histamine, from the cell’s internal fluid (cytoplasm) into synaptic vesicles. Without VMAT2, these neurotransmitters would remain in the cytoplasm, where they could be broken down by enzymes before they can send a signal.
This packaging is a necessary step before neurotransmitters can be released into the synapse, the gap between neurons. Once packaged, vesicles fuse with the cell membrane and release their contents, allowing neurotransmitters to bind to receptors on neighboring neurons and transmit information. This regulated release ensures that brain signals are precise and efficient, much like a postal service sorting letters for delivery.
VMAT2 and Brain Health
Proper VMAT2 function and its regulation of monoamine neurotransmitters are important for brain health. Balanced levels of dopamine, norepinephrine, serotonin, and histamine, maintained by VMAT2, contribute to a range of brain processes. For instance, dopamine regulation is involved in reward, motivation, and motor control, while serotonin influences mood, sleep, and appetite.
Norepinephrine plays a part in alertness and focus, and histamine is involved in arousal and attention. When VMAT2 functions correctly, it ensures these neurotransmitters are available in the right amounts, supporting stable mood, clear thinking, and coordinated movements. A healthy VMAT2 system contributes to maintaining the mental and physical balance that underpins normal brain function.
When VMAT2 Doesn’t Work Properly
When VMAT2 function is impaired, it can lead to imbalances in neurotransmitter levels, contributing to various neurological and psychiatric conditions. If VMAT2 activity is reduced, fewer monoamines are packaged into vesicles, resulting in their breakdown in the cytoplasm and a decrease in their release into the synapse. This depletion of monoamine stores can have consequences for brain signaling.
For example, in Parkinson’s disease, where dopamine-producing neurons degenerate, VMAT2 dysregulation is hypothesized to play a role in motor control issues. Imbalances in monoamine neurotransmitters due to VMAT2 dysfunction are also implicated in psychiatric conditions like schizophrenia and mood disorders. Reduced dopaminergic transmission from VMAT2 inhibitors has been studied for its potential antipsychotic activity.
Targeting VMAT2 with Medications
Understanding VMAT2’s role has led to medications that target this protein. These drugs, VMAT2 inhibitors, reversibly decrease monoamine uptake into synaptic vesicles, reducing their storage and release. This mechanism helps to deplete neurotransmitter levels, particularly dopamine, in nerve terminals.
VMAT2 inhibitors are used to manage hyperkinetic movement disorders, such as tardive dyskinesia (TD) and chorea associated with Huntington’s disease (HD). Tardive dyskinesia, characterized by involuntary movements, often results from long-term use of dopamine-blocking antipsychotic medications. By inhibiting VMAT2, these drugs reduce the excessive dopaminergic signaling thought to contribute to these uncontrolled movements.
Common examples of VMAT2 inhibitors include tetrabenazine, deutetrabenazine, and valbenazine. Tetrabenazine, approved in 2008, was initially used for Huntington’s disease chorea. Deutetrabenazine and valbenazine received FDA approval in 2017 for treating both tardive dyskinesia and Huntington’s disease chorea. While these medications help alleviate symptoms by reducing neurotransmitter availability, they do not stop the progression of underlying neurodegenerative diseases.