SLC18A2

Vesicular monoamine transporter 2 (VMAT2) is a protein that is encoded by the SLC18A2 gene (Solute carrier family 18 member 2) in humans. VMAT2 is a member of the toxin extruding antiporter family [R].

VMAT2 is located in neurons, where it acts as a pump for neurotransmitters, packaging them to be released from the neurons [R]. These neurotransmitters include dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin, histamine and GABA [R;R].

VMAT2 is essential for motor control, stable mood, and autonomic function [R], and protects the neurons from both internal and external toxins [R].

VMAT2 additionally plays a role in the pancreas, where it regulates the production of beta cells that store and release insulin [R].

Reduced VMAT2 function leads to the loss of structure and function of neurons [R], and is linked to many clinical neurological disorders including Parkinson’s Disease [R], Schizophrenia, Bipolar disorder [R], Tardive dyskinesia (TD) [R] and Posttraumatic Stress Disorder [R].

Furthermore, VMAT2 is associated with both anxiety-like behavior [R] and depression [R]. 

VMAT is also associated with METH and cocaine toxicity [R], alcohol and nicotine dependence [R;R].

VMAT2 uses energy from to package monoamines (neurotransmitters) from the neuronal cellular fluid into small sacs for their subsequent release from the neuron [R;R].

VMAT2 is produced primarily brain and histaminergic cells in the gastrointestinal (GI) tract [R].

Complete loss of VMAT2 is lethal in mice [R], while VMAT2-partially deficient mice display progressive neurodegeneration [R].

With aging, there are severe changes in the distribution and the condition of VMAT2 in rats [R].

VMAT2 was nicknamed The God Gene because a variation in the VMAT2 gene supposedly plays a role in one’s openness to spiritual experiences, but this association has not been confirmed in scientific studies [R].

VMAT2 and Neurotoxicity

While the primary function of VMAT2 is to sequester neurotransmitters, this transporter also provides neuroprotection from both internal and external toxicants [R] and protects against neurotoxin-induced cell death [R].

VMAT2 was originally identified by its ability to protect cells from the toxicity of the Parkinsonism-inducing dopamine neurotoxin MPP⁺ [R].

In mice with reduced VMAT2 function, administration of MPP⁺ produces more than twice the dopamine cell loss found in normal mice [R].

VMAT2-deficiency also enhances methamphetamine neurotoxicity in mice [R].

VMAT2 and Parkinsons disease

A decrease in VMAT2 production correlates with susceptibility to Parkinson’s Disease (PD) [R].   

VMAT2 is dysfunctional in brains with Parkinson’s disease [R].

A familial VMAT2 mutation causes an infantile parkinsonian condition with profound motor and cognitive impairments [R].

On the other hand, an increase in VMAT2 level or function protects against the development of PD [R].

Two SNPs in the promoter region of the VMAT2 gene are associated with a reduced PD risk [R], and gain-of-function VMAT2 variants confer protection from PD in women [R].

VMAT2 and other Neurological disorders

Abnormal production of VMAT2 is found in patients with epilepsy [R], and Dementia with Lewy bodies (DLB) [R].

Variations in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder [R].

A VMAT2 risk variant is linked to Posttraumatic Stress Disorder [R].

SNPs in VMAT2 are linked to Schizophrenia, Bipolar disorder [R;R], and Tardive dyskinesia (TD) [R].

A variation within VMAT2 is also associated with cognitive outcomes after severe traumatic brain injury TBI [R].

VMAT2 in Anxiety and Depression

VMAT2 deficiency elicits anxiety-like behavior in zebrafish [R].

VMAT2 deficient mice showed an increase in anxiety in some studies[R], while exhibiting sluggishness, listlessness, and depression [R].

VMAT2 genetic or functional alterations (deficiency) are associated with depression in rats [R], and depression symptoms in men [R].

Reserpine, an irreversible VMAT blocker, prescribed as a medication to lower blood pressure, causes depression in humans [R]. 

VMAT2 and Substance Abuse

Many psychostimulant drugs interact with VMAT2, including methamphetamine (METH), cocaine, and ecstasy (MDMA).

Deletion of VMAT2 results in super-sensitivity to cocaine and amphetamine [R].

VMAT2 inhibitors decrease self-administration of METH in rats [R;R].

On the other hand, elevated VMAT2 levels in mice protects against METH toxicity without enhancing the rewarding effects of the drug [R].

Genetic variants in VMAT2 are linked to alcohol and nicotine dependence [R;R], and certain variants regulating VMAT2 promoter activity are protective against alcoholism [R].

Loss of VMAT2 increased alcohol consumption in male mice [R].

VMAT2 and Diabetes

VMAT2 is an inhibitor of beta cell production in the pancreas [R]. Reserpine and Tetrabenazine (TBZ), both VMAT2 inhibitors, increase production of beta cells, which decreases blood glucose [R].