SLC18A2
Description
The SLC18A2 (solute carrier family 18 member A2) is a protein-coding gene located on chromosome 10.
SLC18A2, also known as vesicular monoamine transporter 2 (VMAT2), is a protein encoded by the SLC18A2 gene. It is an integral membrane protein that transports monoamines, particularly neurotransmitters like dopamine, norepinephrine, serotonin, and histamine, from the cellular cytosol into synaptic vesicles. In nigrostriatal and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is necessary for the vesicular release of the neurotransmitter GABA. SLC18A2 is believed to have at least two distinct binding sites characterized by tetrabenazine (TBZ) and reserpine binding. Amphetamine (TBZ site) and methamphetamine (reserpine site) bind at distinct sites on SLC18A2 to inhibit its function. Inhibitors like tetrabenazine and reserpine reduce the concentration of monoamine neurotransmitters in the synaptic cleft by inhibiting uptake through SLC18A2, preventing storage of neurotransmitters in synaptic vesicles and reducing the quantity released through exocytosis. While many substituted amphetamines induce the release of neurotransmitters from vesicles through SLC18A2 while inhibiting uptake through SLC18A2, they may facilitate the release of monoamine neurotransmitters into the synaptic cleft by reversing the direction of transport through primary plasma membrane transport proteins for monoamines (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter) in monoamine neurons. Other inhibitors like GZ-793A inhibit the reinforcing effects of methamphetamine without producing stimulant or reinforcing effects themselves. Researchers have found that inhibiting the dopamine transporter (but not SLC18A2) will block the effects of amphetamine and cocaine, while disabling SLC18A2 (but not the dopamine transporter) prevents notable action in test animals after amphetamine administration but not cocaine administration. This suggests that amphetamine may be an atypical substrate with little ability to prevent dopamine reuptake via binding to the dopamine transporter but instead uses it to enter a neuron where it then interacts with SLC18A2 to induce efflux of dopamine from their vesicles into the cytoplasm whereupon dopamine transporters with amphetamine substrates attached move this recently liberated dopamine into the synaptic cleft. SLC18A2 is essential for enabling the release of neurotransmitters from the axon terminals of monoamine neurons into the synaptic cleft.
SLC18A2 is an electrogenic antiporter that exchanges one cationic monoamine for two intravesicular protons across the membrane of secretory and synaptic vesicles. It utilizes the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines within vesicles before their release via exocytosis. This protein transports various catecholamines, including dopamine, adrenaline, and noradrenaline, as well as histamine and indolamines like serotonin. It plays a role in regulating the transvesicular monoaminergic gradient that determines the quantal size. SLC18A2 mediates somatodendritic dopamine release in hippocampal neurons, likely as part of a regulated secretory pathway that integrates retrograde synaptic signals. It acts as a primary transporter for striatal dopamine loading, ensuring impulse-dependent release of dopamine at the synaptic cleft. This protein is responsible for histamine and serotonin storage and subsequent corelease from mast cell granules.
SLC18A2 is also known as PKDYS2, SVAT, SVMT, VAT2, VMAT2.
