Monoamine transporter

Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible for the reuptake of their associated amine neurotransmitters (serotonin, dopamine, 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 phosphorylation and posttranslational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs, a line that can become quite blurred in many cases. 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. Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible for the reuptake of their associated amine neurotransmitters (serotonin, dopamine, 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 phosphorylation and posttranslational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs, a line that can become quite blurred in many cases. 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. There are several different monoamine transporters located along the plasma membrane, each belonging to the family of Na +/Cl − -dependent substrate-specific neuronal membrane transporters. DAT is responsible for the Na +/Cl − -dependent reuptake of extracellular dopamine (DA). DAT can also transport extracellular norepinephrine. DATs can be found in the central nervous system (CNS), where they are localized in the substantia nigra and ventral tegmental area (VTA). DATs are also found in the peripheral nervous system (PNS) where they are localized in the stomach, pancreas, as well as in lymphocytes. Various kinases have been linked to DAT regulation including PKA, PKC, PI-3K, ERK1, ERK2, Akt, CaMKII, CDK5, and MAPK. NET is responsible for the Na +/Cl − -dependent reuptake of extracellular norepinephrine (NE). NET can also reuptake extracellular DA. Within the CNS, NET is localized to the dendrites and axons found in both the hippocampus and cortex. Peripherally, NET can be found in sympathetic peripheral neurons, the adrenal medulla, the lung, the placenta, and the vas deferens. Regulation of NET has been linked to MAPKs, insulin, PKC, and angiotensin II. SERT is responsible for the reuptake of extracellular serotonin (5-HT) in a Na +/Cl − -dependent process. In the CNS, SERT is found localized in the cerebral cortex, CA1 and CA3 regions of the hippocampus, as well as the median and dorsal raphe nuclei. In the PNS, SERT is localized to the intestinal tract, adrenal glands, placenta, lung, and platelets . Expression of SERT in platelets is used as a means to reacquire 5-HT from the extracellular environment and later used in platelet activation. Regulation of SERT has been linked to acute depletion of intracellular Ca Na 2+, calmodulin inhibition, CaMKII, Src, p38 MAP kinase, PKC, and activation of NOS/cGMP. Monoamine transporters are members of the group of Na +/Cl − -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family. 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. 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. 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. 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. 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. Similar phosphorylation events occur in DAT and NET, decreasing the cells transport capacity of MAs.