Monoamine transporter

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Dopamine Transporter (DAT-6) Dopamine Transporter.jpg
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. [1] MAT regulation generally occurs through protein phosphorylation and post-translational modification. [2] 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 [3] ("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. [1] [4]

Contents

Types

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. [2]

Function

Dopamine transporter (DAT)

DAT is responsible for the Na +/Cl -dependent reuptake of extracellular dopamine (DA). [2] 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. [2] Various kinases have been linked to DAT regulation including PKA, PKC, PI-3K, ERK1, ERK2, Akt, CaMKII, CDK5, and MAPK. [2]

Norepinephrine transporter (NET)

NET is responsible for the Na +/Cl -dependent reuptake of extracellular norepinephrine (NE). [2] 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. [1] [2] Regulation of NET has been linked to MAPKs, insulin, PKC, and angiotensin II. [2]

Serotonin transporter (SERT)

SERT is responsible for the reuptake of extracellular serotonin (5-HT) in a Na +/Cl -dependent process. [2] 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 . [1] [2] 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. [2]

Structure and mechanism

Dopamine transporter crystal structure. Extracellular, transmembrane, and intracellular regions shown in turquoise, blue, and pink, respectively. Based on structure from Penmansta et al. (Nature, 2013) Dopamine Transporter Crystal Structure.png
Dopamine transporter crystal structure. Extracellular, transmembrane, and intracellular regions shown in turquoise, blue, and pink, respectively. Based on structure from Penmansta et al. (Nature, 2013)

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.

MATGeneSizeHuman Chromosome
DAThDAT620 amino acids5p15.3 [2]
SERThSERT630 amino acids17q11.2 [2]
NEThNET617 amino acids16q12.2 [2]

Associated disorders and treatments

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 ADHD, depression, drug abuse, Parkinson's disease, Schizophrenia, and Tourette's syndrome. Evidence supporting this belief includes that monoamine transporters, DAT, NET, and SERT, are important target sites for therapeutic drugs used in the treatment of mood disorders. Several drugs are used to treat disease symptoms by blocking monoamine transporters, which results in an increase in extracellular monoamines. [7] 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. [1]

Attention deficit hyperactivity disorder

It has been observed that the hyperactivity, inattention, and impulsivity in ADHD is related to abnormal DAT function and regulation. Dopaminergic hypofunction in the frontal cortex and basal ganglia is a neurobiological feature observed in ADHD. [8] Psychostimulants that potently inhibit DAT, such as methylphenidate and amphetamine, are efficacious in treating ADHD. Methylphenidate (Ritalin) inhibits both DAT and NET, which results in an increase in extracellular dopamine and norepinephrine that can readily bind postsynaptic cells. Methylphenidate targets DAT as a non-selective reuptake inhibitor. [2] Methylphenidate is not an inhibitor of SERT. [8]

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. [9] 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. [10]

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. [2]

Psychostimulants

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. Large increases in synaptic dopamine result in increased stimulation of target neurons believed to create the sensations of cocaine. [1]

Cocaine

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]

Amphetamine

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 TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine binds to TAAR1, it reduces post-synaptic receptor firing rate and triggers protein kinase A and protein kinase C signaling, resulting in transporter phosphorylation. Phosphorylated transporters then either operate in reverse or withdraw into the presynaptic neuron and cease transport. When amphetamine enters the synaptic vesicles through VMAT2, monoamines are released into the cytosol. [11] [12]

Research history

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]

16e JZ-IV-10 chemical structure.png
16e
Blough 2002 Phenyltropane Carroll 4b.svg
Blough 2002

Double and triple MAT agents (a.k.a. SNRIs and TRIs)

Below are examples of drugs that act directly by inhibiting two or more MATs simultaneously. Serotonin-norepinephrine re-uptake inhibitors (SNRIs) act by blocking both SERTs and NETs. Triple re-uptake inhibitors (TRIs) act by blocking DATs, NETs, and SERTs simultaneously. Most modern antidepressant drugs work on the principle of blocking re-uptake transporters. SSRI's such as Fluoxetine (Prozac) and SNRI's as with Venlafaxine are the main types of drugs given in first line depression and anxiety treatment.

See also

Related Research Articles

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Reuptake</span> Reabsorption of a neurotransmitter by a neurotransmitter transporter

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Norepinephrine reuptake inhibitor</span> Class of drug

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter (DAT) also is a membrane-spanning protein coded for in the human by the SLC6A3 gene,, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

<span class="mw-page-title-main">Serotonin reuptake inhibitor</span> Class of drug

A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

A reuptake inhibitor (RI) is a type of drug known as a reuptake modulator that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective DRAs are currently known. Many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known, however. Serotonin–dopamine releasing agents are much rarer and are not selective for monoamine release. Examples of NDRAs include amphetamine and methamphetamine, and an example of an SNDRA is MDMA. The most selective dopamine releaser is 4-methylaminorex, but it also has considerable activity as a norepinephrine releaser. These drugs are frequently used for recreational purposes and encountered as drugs of abuse.

<span class="mw-page-title-main">Plasma membrane monoamine transporter</span> Protein-coding gene in the species Homo sapiens

The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). Unlike other members of the ENT family, it is impermeable to most nucleosides, with the exception of the inhibitory neurotransmitter and ribonucleoside adenosine, which it is permeable to in a highly pH-dependent manner.

Reverse transport, or transporter reversal, is a phenomenon in which the substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter. Transporter reversal typically occurs when a membrane transport protein is phosphorylated by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins.

<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

<span class="mw-page-title-main">RTI-83</span> Chemical compound

RTI-83 is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related neurotransmitter noradrenaline. With a binding affinity (Ki) of 55 nM at DAT and 28.4 nM at SERT but only 4030 nM at NET, RTI-83 has reasonable selectivity for DAT/SERT over NET

<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

References

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