Vesicular monoamine transporters: Structure‐function, pharmacology, and medicinal chemistry

Abstract

Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. VMAT1 is preferentially expressed in neuroendocrine cells and VMAT2 is primarily expressed in the CNS. The neurotoxicity and addictive properties of various psychostimulants have been attributed, at least partly, to their interference with VMAT2 functions. The quantitative assessment of the VMAT2 density by PET scanning has been clinically useful for early diagnosis and monitoring of the progression of Parkinson's and Alzheimer's diseases and drug addiction. The classical VMAT2 inhibitor tetrabenazine has long been used for the treatment of chorea associated with Huntington's disease in UK, Canada and Australia and recently approved in the US. The VMAT2 imaging may also be useful for exploiting the onset of diabetes mellitus, since VMAT2 is also expressed in the β-cells of the pancreas. VMAT1 gene SLC18A1 is a locus with strong evidence of linkage with schizophrenia and thus, the polymorphic forms of the VMAT1 gene may confer susceptibility to schizophrenia. This review summarizes the current understanding of the structurefunction relationships of VMAT2, and the role of VMAT2 on addiction and psychostimulant induced neurotoxicity, and the therapeutic and diagnostic applications of specific VMAT2 ligands. The evidence for the linkage of VMAT1 gene with schizophrenia and bipolar disorder I are also discussed.

Electrophysiological Actions of Synthetic Cathinones on Monoamine Transporters

“…The respective reuptake transporters for NE, DA and 5HT (i.e., NET, DAT, and SERT) are located at perisynaptic sites (6, 7), whence monoamines are re-packaged into synaptic vesicles via vesicular monoamine transporters (VMATs). In particular, the vesicular monoamine transporter 2 (VMAT2), which is primarily found in the CNS, is responsible for neurotransmitter reuptake into synaptic vesicles that are poised for docking and release in dopaminergic, serotonergic and noradrenergic neurons (8). …”

Analysis of Amperometric Spike Shapes to Release Vesicles

“…CAs are synthesized by neurons and neurosecretory cells in which tyrosine is converted into ldihydroxyphenylalanine (l-DOPA) by a tyrosine hydroxylase, and then converted into dopamine by a DOPA decarboxylase (see review by [1]). In neurons and neurosecretory cells, dopamine is transported from the intracellular space into membrane-bound vesicles by specific monoamine transporters (see review by [2]). These CAfilled vesicles are available for rapid fusion with the neuronal membrane when a stimulating trigger causes an increase in intracellular Ca 2 + [3].…”

Amphetamines: Potent Recreational Drug of Abuse

“…Some pathways like serotonergic pathways may contribute to the calming effect. Amphetamine interacts with vesicular monoamine transporter (VMAT) enzymes to enhance release of non-exocytotic release of dopamine (DA) and 5-HT from vesicles [11,12].…”