Monoamine transporter

Monoamine transporters (MATs) are

• The dopamine transporter, DAT.
• The norepinephrine transporter, NET.
• The serotonin transporter, SERT.

DAT is responsible for the Na ⁺/Cl ⁻ -dependent reuptake of extracellular dopamine (DA).

NET is responsible for the Na ⁺/Cl ⁻ -dependent reuptake of extracellular norepinephrine (NE).

SERT is responsible for the reuptake of extracellular serotonin (5-HT) in a Na ⁺/Cl ⁻ -dependent process.

Monoamine transporters are members of the group of Na ⁺/Cl ⁻ -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family.^[5] MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH₂ and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells. All MATs contain sites for protein kinase phosphorylation by cAMP-dependent protein kinase, protein kinase C (PKC) and Ca²⁺/calmodulin-dependent protein kinase.^[2][1]

MATs are responsible for the uptake of monoamines by the sequential binding and co-transport of Na ⁺ and Cl ⁻ ions. The ion concentration gradient generated by the plasma membrane Na⁺/K⁺ ATPase provides the driving force for the transporter-mediated monoamine uptake.^[1][6] In the case of NET and SERT one Na⁺ and one Cl⁻ ion are transported into the cell with one NE or 5-HT respectively. In the case of DAT two Na⁺ and one Cl⁻ ion are transported along with one DA. When ionic gradients are altered (extracellular K⁺ increases or extracellular Na⁺ or Cl⁻ decreases) transporters can function in reverse resulting in a net efflux of substrates and ions out of a neuron.^[1]

To return to an outwardly facing conformation SERT requires the transport of intracellular K⁺. There is no evidence that the other transporters have such a requirement.^[1]

Phosphorylation plays a key role in MAT function. When SERT is phosphorylated by the PKC-dependent pathway SERT internalization occurs. The internalization of SERT reduces 5-HT uptake.^[2] Similar phosphorylation events occur in DAT and NET, decreasing the cells transport capacity of MAs.

Monoamine transporters are believed to be factors in several neurological conditions due to their role in reuptake of the monoamines dopamine, noradrenaline, and serotonin. These conditions include

NET regulation is linked to altered dopamine transmission and schizophrenia-like behaviors. Nisoxetine is a NET inhibitor and reverses some schizophrenia-linked behavior. NET activities regulate NE as well as DA equilibrium. In addition, for normal DA clearance a functional DAT is necessary which suggests that DAT dysfunction may contribute to schizophrenia.^[2]

DAT is also the target of several "DAT-blockers" including amphetamine and cocaine. These chemicals inhibit the action of DAT and, to a lesser extent, the other monoamine transporters, but their effects are mediated by separate mechanisms.

Monoamine transporters are established targets for many pharmacological agents that affect brain function, including the psychostimulants cocaine and amphetamine. Cocaine and amphetamine employ different mechanisms that both result in an increase in extracellular monoamines by decreasing reuptake. Psychostimulants affect primarily DAT, although there is some inhibition at SERT and NET. A large increase of synaptic dopamine results in an increased stimulation of target neurons believed to create the sensations of cocaine.^[1]

The stimulatory and euphoric effects of cocaine are created when cocaine inhibits the reuptake of dopamine by DAT, which results in an increase in extracellular dopamine. Dopamine can then more readily bind neurons, which overstimulates the cells. Cocaine is a non-selective, competitive inhibitor of monoamine transporters, sharing a similar mechanism with that of methylphenidate. Cocaine interacts with DAT, SERT, and NET, although the behavioral and reinforcing effects of cocaine depend on its inhibition of DAT and the increase in extracellular dopamine.^[1]

In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through monoamine transporters, competing for reuptake with neurotransmitters. Once inside, it binds to

The field of monoamine transporter research began roughly five decades ago^[timeframe?] with Julius Axelrod's research on NETs. Axelrod eventually received his Nobel Prize for this research, which led to the discovery of DATs and SERTs as well as consequences associated with antidepressant and psychostimulant interactions with MAT proteins. Since Axelrod's initial studies, understanding the pharmacological and functional properties of MAT proteins have been essential in the discovery of therapeutic treatment of many mental disorders.^[1] During the 1990s various cloning techniques using MATs have elucidated the genetic structure of these proteins. In 1991 Susan Amara and her colleagues determined the amino acid sequence of NET, discovering its relatively high coding similarities to that of the GABA transporter.^[1]

Current research is underway to understand how MATs function and are regulated by looking at newly discovered structural and functional domains of these proteins.^[1][13] Over the last decade, the availability of targeted disruption of monoamine transporter genes in animal models as well as in vivo imaging approaches have shown progress in studies associated with psychiatric and movement disorders.^[1] Ongoing research is attempting to clarify the extent to which kinase cascades, transporter interacting proteins, and phosphorylation contribute to MAT regulation.^[2]

Below are examples of drugs that act directly by inhibiting two or more MATs simultaneously. Serotonin-norepinephrine re-uptake inhibitors (

• PRC200-SS is an example of an SNRI.
• JNJ-7925476 is an example of a TRI
• nocaine-modafinil hybrids such as 16e^[14][15]
• Blough (2002) showed that MATs exhibit a "remote phenyl binding domaine"[16]

• Vesicular monoamine transporter (VMAT)
• Plasma membrane monoamine transporter (PMAT)
• Extraneuronal monoamine transporter
  (EMT)