Monoamine transporter
Encyclopedia
Monoamine transporters (MATs) are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitter
s. 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 the targets of many therapeutic drugs associated with mood disorders such as fluoxetine
(Prozac) and methylphenidate
(Ritalin). Synthetic compounds such as methamphetamine
and cocaine
can also target MATs.
(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.
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.
, 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
.
-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.
, 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. 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.
hypofuction in the frontal cortex and basal ganglia
is a neurobiological feature observed in ADHD. Psychostimulants, methylphenidate
and amphetamines, which potently inhibit DAT 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
. Methylphenidate is not an inhibitor of SERT.
(Prozac), citalopram
(Celexa), and fluvoxamine
. 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.
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.
DAT is also the target of several “DAT-blockers” including amphetamines 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 amphetamines. Cocaine and amphetamines 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 and amphetamines.
(ice), methylenedioxymethamphetamine
(MDMA; ecstacy), cathinone
, and methylphenidate (Ritalin). Once transported into the synaptic terminal of the neuron, amphetamines are enclosed in synaptic vesicles and act as weak bases on the vesicles. This causes a redistribution of vesicular monoamines from the synaptic vesicle into the cytoplasm of the synaptic terminal. An elevation in cytoplasmic monoamine concentration leads to the reversal of monoamine transporters. As a result, there is a massive release of monoamine neurotransmitters into the extracellular space. Excess monoamine neurotransmitters in the synaptic cleft leads to overstiumulation of the cells.
’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. During the 1990’s 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 GABA
.
Current research is underway to understand how MATs function and are regulated by looking at newly discovered structural and functional domains of these proteins. 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. Ongoing research is attempting to clarify the extent to which kinase cascades, transporter interacting proteins, and phosphorylation contribute to MAT regulation.
Monoamine neurotransmitter
thumb|right|350px| A phylogenetic tree showing how a number of monoamine receptors are related to each other.Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain...
s. Three major classes of MATs (SERT, DAT, NET) are responsible for the reuptake of their associated amine neurotransmitters (serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, 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
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
. Due to their significance in neuronal signaling, MATs are the targets of many therapeutic drugs associated with mood disorders such as fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac) and methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
(Ritalin). Synthetic compounds such as methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
can also target MATs.
Types
There are several different monoamine transporters each belonging to the family of Na +/Cl - -dependent substrate-specific neuronal membrane transporters.- The dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
transporter, DATDopamine transporterThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
. - The norepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
transporter, NETNorepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
. - The serotonin transporter, SERTSerotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
.
Dopamine transporter (DAT)
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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS), where they are localized in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
and ventral tegmental area (VTA). DATs are also found in the peripheral nervous system (PNS
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
) where they are localized in the stomach, pancreas, as well as in lymphocytes. Various kinases have been linked to DAT regulation including PKA, PKC
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
, PI-3K, ERK1, ERK2, Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
, CaMKII, CDK5, and MAPK.
Norepinephrine transporter (NET)
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 hippocampusHippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and cortex. Peripherally, NET can be found in sympathetic peripheral neurons, the adrenal medulla
Adrenal medulla
The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...
, the lung, the placenta, and the vas deferens
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
. Regulation of NET has been linked to MAPKs, insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, PKC, and angiotensin II.
Serotonin transporter (SERT)
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 cortexCerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, CA1 and CA3 regions of the hippocampus, as well as the median and dorsal raphe nuclei
Raphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...
. 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
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
inhibition, CaMKII, Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
, p38 MAP kinase, PKC, and activation of NOS
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
/cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
.
Structure and mechanism
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 cAMPCyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
-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.
| MAT | Gene | Size | Human Chromosome |
|---|---|---|---|
| DAT | hDAT | 620 amino acids | 5p15.3 |
| SERT | hSERT | 630 amino acids | 17q11.2 |
| NET | hNET | 617 amino acids | 16q12.2 |
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 5-hydroxytryptamine. These conditions include ADHD, depression, drug abuseDrug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
, Parkinson’s disease, Schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, 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. In addition, the levels of monoamine transporters have been shown to be altered in many of these psychiatric and neurological conditions. Finally, polymorphic
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
variations in monoamine transporter genes have been proposed to be associated with conditions such as ADHD and depression.
Attention deficit hyperactivity disorder
It has been observed that the hyperactivity, inattention, and impulsivity in ADHD is related to abnormal DAT function and regulation. DopaminergicDopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
hypofuction in the frontal cortex and basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
is a neurobiological feature observed in ADHD. Psychostimulants, methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
and amphetamines, which potently inhibit DAT 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
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
. Methylphenidate is not an inhibitor of SERT.
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 fluoxetineFluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac), citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa), and fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
. 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
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
are being used as effective antidepressants that selectively inhibit both SERT and NET. The tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
desipramine
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
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. NisoxetineNisoxetine
Nisoxetine is a drug which inhibits the reuptake of norepinephrine . It is a racemic compound with two isomers...
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.
Psychostimulants
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
. 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
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
and amphetamines. Cocaine and amphetamines 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 and amphetamines.
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. 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.Amphetamines
Amphetamines function as substrates for monoamine transporters. The family of amphetamines includes a wide variety of subtypes including D-amphetamine (speed), methamphetamineMethamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
(ice), methylenedioxymethamphetamine
Methylenedioxymethamphetamine
MDMA is an entactogenic drug of the phenethylamine and amphetamine class of drugs. In popular culture, MDMA has become widely known as "ecstasy" , usually referring to its street pill form, although this term may also include the presence of possible adulterants...
(MDMA; ecstacy), cathinone
Cathinone
Cathinone, or Benzoylethanamine, is a monoamine alkaloid found in the shrub Catha edulis and is chemically similar to ephedrine, cathine and other amphetamines. Cathinone induces the release of dopamine from striatal preparations that are prelabelled either with dopamine or its precursors. It is...
, and methylphenidate (Ritalin). Once transported into the synaptic terminal of the neuron, amphetamines are enclosed in synaptic vesicles and act as weak bases on the vesicles. This causes a redistribution of vesicular monoamines from the synaptic vesicle into the cytoplasm of the synaptic terminal. An elevation in cytoplasmic monoamine concentration leads to the reversal of monoamine transporters. As a result, there is a massive release of monoamine neurotransmitters into the extracellular space. Excess monoamine neurotransmitters in the synaptic cleft leads to overstiumulation of the cells.
Research history
The field of monoamine transporter research began roughly five decades ago with Julius AxelrodJulius Axelrod
Julius Axelrod was an American biochemist. He won a share of the Nobel Prize in Physiology or Medicine in 1970 along with Bernard Katz and Ulf von Euler...
’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. During the 1990’s 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 GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
.
Current research is underway to understand how MATs function and are regulated by looking at newly discovered structural and functional domains of these proteins. 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. Ongoing research is attempting to clarify the extent to which kinase cascades, transporter interacting proteins, and phosphorylation contribute to MAT regulation.
Double and triple MAT agents (aka 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.- PRC200-SS is an example of an SNRI.
- JNJ-7925476JNJ-7925476JNJ-7925476 is a TRI antidepressant currently under development by Johnson & Johnson.These molecules were first prepared by Bruce E. Maryanoff, et al. during the late 1970s – 1980's...
is an example of a TRI - nocaineNocaine-CPCA is a stimulant drug similar in structure to RTI-31, but lacking the two-carbon bridge of the tropane skeleton This compound was first developed as a substitute agent for cocaine.Since this time a large number of substituted phenylpiperidine derivatives have been discovered, hybridizing the...
-modafinilModafinilModafinil is an analeptic drug manufactured by Cephalon, and is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea...
hybrids such as 16e
- Blough (2002) showed that MATs exhibit a "remote phenyl binding domaine"
See also
- Glutamate transporterGlutamate transporterExcitatory amino-acid transporters , formerly known as Glutamate transporters, belong to the family of neurotransmitter transporters. They serve to terminate the excitatory neurotransmitter signal by removal of glutamate from the neuronal synapse into Glia cells.In details, the EAATs are...
- Vesicular monoamine transporterVesicular monoamine transporterThe vesicular monoamine transporter is a transport protein integrated into the membrane of intracellular vesicles of presynaptic neurons. It acts to transport monoamines into the synaptic vesicles.-Monoamines:...
- Phenyltropanes
- The less-specific monoamine transporter, PMATPlasma membrane monoamine transporterThe plasma membrane monoamine transporter is a low-affinity monoamine transporter protein. It is also known as human equilibrative nucleoside transporter-4...
.