Vesicular Monoamine Transporter (VMAT) Function
Vesicular monoamine transporters (VMATs) are H+-coupled secondary active transporters that package monoamine neurotransmitters—including dopamine, serotonin, norepinephrine, epinephrine, and histamine—from the neuronal cytoplasm into presynaptic vesicles for storage and subsequent exocytotic release. 1, 2, 3
Primary Transport Mechanism
VMAT proteins function as proton-coupled antiporters, exchanging two luminal H+ ions for one cytoplasmic monoamine molecule, driven by the electrochemical proton gradient established by the vacuolar H+-ATPase 3
The transport cycle involves conformational transitions between cytoplasm-facing, occluded, and lumen-facing states, with the proton gradient driving the shift from lumen-facing back to cytoplasm-facing conformations 2, 3
Two Distinct Isoforms
VMAT1 (SLC18A1) and VMAT2 (SLC18A2) differ in their regional expression, quantity, and functional properties 1
VMAT2 is the predominant neuronal isoform and is specifically expressed in monoaminergic neurons of the central and peripheral nervous systems, including dopaminergic neurons of the substantia nigra and ventral tegmental area, serotonergic neurons of the raphe nuclei, noradrenergic neurons of the locus coeruleus, and histaminergic neurons of the tuberomammillary nucleus 4, 5
VMAT1 is primarily expressed in neuroendocrine cells, including chromaffin cells of the adrenal medulla 4
Critical Neuroprotective Function
Beyond neurotransmission, VMAT2 provides essential neuroprotection by sequestering cytosolic monoamines (particularly dopamine) that would otherwise undergo auto-oxidation and generate reactive oxygen species causing oxidative stress 6
VMAT2 can translocate exogenous toxicants away from cytosolic sites of action—for example, sequestering MPP+ (the active metabolite of MPTP) within vesicles prevents it from disrupting mitochondrial function in dopamine neurons 6
VMAT2-deficient mice demonstrate enhanced neurotoxicity from methamphetamine, confirming the protective role of vesicular sequestration against both endogenous and exogenous toxicants 6
Clinical and Diagnostic Significance
VMAT2 serves as both a therapeutic target and diagnostic marker for numerous neurological and psychiatric conditions 4, 1
Radiolabeled VMAT2 ligands (such as [11C]dihydrotetrabenazine) are used in PET imaging to visualize monoaminergic neurons and quantify beta cell mass in pancreatic islets, where VMAT2 is selectively expressed 4
In nuclear medicine imaging, MIBG (meta-iodobenzylguanidine) is stored in neurosecretory granules via VMAT1 and VMAT2, with vesicular uptake being predominant in pheochromocytomas and paragangliomas 4
Pharmacological Targeting
Inhibitors of VMAT2 include reserpine, tetrabenazine, and ketanserin, which bind at distinct sites and trap VMAT2 in different conformational states 2
Reserpine occupies the substrate-binding pocket and locks VMAT2 in a cytoplasm-facing state, while tetrabenazine binds in a VMAT2-specific pocket and traps it in an occluded state 2
Reversible VMAT2 inhibitors are FDA-approved for treating moderate to severe tardive dyskinesia associated with antipsychotic therapy 4
Amphetamine inhibits VMAT2 (along with dopamine and norepinephrine transporters and monoamine oxidase), which contributes to its mechanism of action in ADHD and narcolepsy treatment 7
Drug Interactions and Clinical Implications
Many medications modify VMAT uptake and storage, including opioids, tricyclic antidepressants, sympathomimetics, antipsychotics, and antihypertensive agents, which can interfere with MIBG imaging used to detect neuroendocrine tumors 4
Labetalol must be stopped 10 days prior to MIBG administration as it causes false-negative scans 4