thumb|280px|right|Dopamine Transporter (DAT-6)
Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters (serotonin, dopamine, and norepinephrine). MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms (Adderall, Dexedrine) and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA ("ecstasy", "molly") and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
Types
There are several different monoamine transporters located along the plasma membrane, each belonging to the family of Na <sup>+</sup>/Cl <sup>−</sup> -dependent substrate-specific neuronal membrane transporters. MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH<sub>2</sub> 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 Ca<sup>2+</sup>/calmodulin-dependent protein kinase. In the case of NET and SERT one Na<sup>+</sup> and one Cl<sup>−</sup> ion are transported into the cell with one NE or 5-HT respectively. In the case of DAT two Na<sup>+</sup> and one Cl<sup>−</sup> ion are transported along with one DA. When ionic gradients are altered (extracellular K<sup>+</sup> increases or extracellular Na<sup>+</sup> or Cl<sup>−</sup> decreases) transporters can function in reverse resulting in a net efflux of substrates and ions out of a neuron. In addition, the levels of monoamine transporters have been shown to be altered in many of these psychiatric and neurological conditions. Finally, polymorphic variations in monoamine transporter genes have been proposed to be associated with conditions such as ADHD and depression.
Depression
It has been observed that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the CNS, particularly of serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressant and include fluoxetine (Prozac), citalopram (Celexa), and fluvoxamine (Luvox). These drugs inhibit the reuptake of serotonin from the extracellular space into the synaptic terminal by selectively inhibiting SERT. It has been recently observed that serotonin, norepinephrine, and dopamine may all be involved in depression. Therefore, drugs such as venlafaxine and paroxetine are being used as effective antidepressants that selectively inhibit both SERT and NET. The tricyclic antidepressant desipramine is an antidepressant drug that is a relatively selective inhibitor of NE uptake. Studies of inhibition of NET correlate with antidepressant activity.
Schizophrenia
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.
Research history
The field of monoamine transporter research began roughly five decades ago 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. 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.
- Blough (2002) showed that MATs exhibit a "remote phenyl binding domaine"
See also
- Vesicular monoamine transporter (VMAT)
- Plasma membrane monoamine transporter (PMAT)
- Extraneuronal monoamine transporter (EMT)