Norepinephrine transporter
Encyclopedia
The norepinephrine transporter (NET), also known as solute carrier family 6 member 2 (SLC6A2), is a protein
that in humans is encoded by the SLC6A2 gene
.
NET is a monoamine transporter
and is responsible for the Na+/Cl–-dependent reuptake
of extracellular norepinephrine
(NE). NET can also reuptake extracellular dopamine
(DA). The reuptake of these two neurotransmitters
is essential in regulating concentrations in the synaptic cleft. NETs, along with the other monoamine transporters, are the targets of many antidepressants and recreational drugs. In addition, a deficiency of NET is associated with many affective and autonomic disorders such as orthostatic intolerance
and ADHD. There is evidence that single-nucleotide polymorphisms in the NET gene (SLC6A2) may be an underlying factor in some of these disorders.
. Based on the nucleotide and amino acid sequence, the NET transporter consists of 617 amino acids with 12 membrane-spanning domains. The structural organization of NET is highly homologous to other members of a sodium/chloride-dependent family of neurotransmitter transporters, including dopamine, epinephrine, serotonin
and GABA transporters.
, T
, C
or G
). NET proteins with an altered amino acid sequence (more specifically, a missense mutation
) could potentially be associated with various diseases that involve abnormally high or low plasma levels of norepinephrine
due to altered NET function. NET SNPs and possible associations with various diseases are an area of focus for many research projects. There is evidence suggesting a relationship between NET SNPs and various disorders such as ADHD psychiatric disorders, postural tachycardia
and orthostatic intolerance
. The SNPs rs3785143 and rs11568324 have been related to attention-deficit hyperactivity disorder
. Thus far, however, the only confirmed direct association between a SNP and a clinical condition is that of the SNP, Ala457Pro, and orthostatic intolerance. Thirteen NET missense mutations have been discovered so far.
and panic disorder
.
(-) group and carboxyl
(-COOH) group. In addition, there is a large extracellular loop located between TMD 3 and 4. The protein is composed of 617 amino acids
.
back into the presynaptic neuron. As much as 90% of the norepinephrine released will be taken back up in the cell by NET. NET functions by coupling the influx of Na+ and Cl– with the transport of norepinephrine. This occurs at a fixed ratio of 1:1:1. Both NET and DAT
can transport norepinephrine and dopamine. The reuptake of norepinephrine and dopamine is essential in regulating the concentration of monoamine neurotransmitters in the synaptic cleft. The transporter also helps maintain homeostatic balances of the presynaptic neuron.
Norepinephrine (NE) is released from noradrenergic neurons that innervate both the CNS
and PNS
. NE, or noradrenaline (NA), has an important role in controlling mood, arousal, memory, learning, and pain perception. NE is a part of the sympathetic nervous system
. Dysregulation of the removal of norepinephrine by NET is associated with many neuropsychiatric diseases. In addition, any antidepressants and recreational drugs compete for the binding of NET with NE.
, and dendrites
of the neuron. NETs are located away from the synapse, where norepinephrine is released, closer to the plasma membrane of the cell. This requires norepinephrine to diffuse from the site it is released to the transporter for reuptake. Norepinephrine transporters are confined to the nerves of the sympathetic system, and those innervating the adrenal medulla, lung, and placenta.
(PKC). PKC has been shown to inhibit NET function by sequestration of the transporter from the plasma membrane. The amino acid sequence of NET has shown multiple sites related to protein kinase phosphorylation. Post-translational modifications can have a wide range of effects on the function of the NET, including the rate of fusion of NET-containing vesicles with the plasma membrane, and transporter turnover.
(a subcategory of dysautonomia
) characterized by the onset of symptoms upon standing. Symptoms include fatigue, lightheadedness, headache, weakness, increased heart rate/heart palpitations, anxiety, and altered vision. Oftentimes, patients have high plasma norepinephrine
(NE) concentrations (at least 600 pg/ml) in relation to sympathetic outflow upon standing, suggesting OI is a hyperadrenergic
condition.
The discovery of identical twin sisters both suffering from OI suggested a genetic basis for the disorder. A missense mutation
on the NET gene (SLC62A) was discovered in which an alanine
residue was replaced with a proline
residue (Ala457Pro) in a highly conserved region of the transporter. The patients’ defective NET had only 2% of the activity of the wild-type
version of the gene. The genetic defect in the NET protein results in decreased NET activity that could account for abnormally high NE plasma levels in OI. However, 40 other OI patients did not have the same missense mutation, indicating other factors contributed to the phenotype in the identical twins. This discovery of the linkage with NET mutations that results in decreased norepinephrine reuptake
activity and orthostatic intolerance suggests faulty NE uptake mechanisms can contribute to cardiovascular disease.
medications act to raise noradrenaline, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors
(NDRIs), norepinephrine reuptake inhibitors
(NRIs or NERIs) and the tricyclic antidepressants (TCAs). These medications prevent NET from functioning normally, resulting in higher extracellular concentrations of NE. Noradrenaline therefore remains in the synapse longer, allowing it to reach more normal levels. Since the noradrenaline transporter is responsible for most of the dopamine clearance in the prefrontal cortex, SNRIs would also raise dopamine levels in synapses there. However, dopamine in most brain regions is cleared primarily by the dopamine transporter
, which works roughly ten times faster.
For many years, the number one choice in treating mood disorders like depression was through the uptake of TCAs, such as desipramine
(Norpramin), nortriptyline
(Arentyl, Pamelor), protriptyline (Vivactil) and amoxapine
(Asendin). However, currently far more potent drugs have been developed in the US, most notably the discovery of selective serotonin reuptake inhibitors (SSRIs). SSRIs affect the communication between chemical messengers in the brain by regulating how much of a certain chemical messenger enters the brain. SSRIs regulate serotonin levels in the brain, which seems to aid the brain in exchanging messages more efficiently and in turn livens mood. Drugs such as fluoxetine
and paroxetine
are both very impelling in treating mood disorders because they reduce many of the side effects one receives compared to using TCAs to treat such mood disorders.
The strong NET inhibitor atomoxetine (Strattera) has been approved by the FDA to treat ADHD in adults. It works to increase one's ability to focus, decrease any impulsiveness, and lessen hyperactivity in both children and adults who suffer from ADHD. It is the first ADHD drug to be developed that reduces any risk of substance abuse for patients who continually take atomoxetine for their ADHD. The FDA approved another drug called Vyvanse specifically prescribed to children between the ages of 6 and 12 to treat ADHD. Both drugs for adults and children had common side effects similar to decreased appetite, bad sleeping habits, stomachaches and headaches. Other common drugs that have been previously prescribed to treat ADHD in adults and children include Methylphenidate
(Ritalin, Metadate, Concerta, Daytrana
), Amphetamine
(Adderall
) and Dextroamphetamine
(Dexadrine, Detrostat).
The role of NE in schizophrenia
has not been fully understood, but has stimulated research into this topic. The only relationship that has been understood between researchers is that there is a positive correlation between increased NE levels in the brain and activity of schizophrenia. Before the age of modern treatment of schizophrenia, patients that were mentally ill were not treated and instead that were hidden away in their homes. Old treatments often included sedatives, electroconvulsive therapy
(ECT), artificially induced comas and frontal lobotomies. Unfortunately, the side effects of these treatments usually outweighed the therapeutic benefits of these treatments. The first breakthrough for schizophrenia treatment was the discovery of the antipsychotic
drug called Chlorpromazine
(CPZ) in 1979, which is still in common use today. Another drug developed from the class of atypical antipsychotic
drug called Clozapine
. This drug works to help patients who have tried to injure/kill themselves before from getting no prior treatment. It works similarly to SSRIs by regulating the concentrations of certain chemical messengers in the brain.
is a powerful psychostimulant and known to be one of the most widely abused substances. Cocaine is a nonselective, competitive antagonist
of norepinephrine
, serotonin
, and dopamine
transport. This thwarts the absorption of these chemicals into the presynaptic terminal and allows a large concentration of dopamine, serotonin and norepinephrine to build up in the cell. The potential for cocaine addiction is thought to be a result of its effects on dopamine transporters
in the CNS, while it has been suggested that the life-threatening cardiovascular effects of cocaine may involve the inhibition of NETs at sympathetic and CNS autonomic synapses.
Amphetamines have a similar effect on norepinephrine
levels compared to that of cocaine
in that they both increase NE levels in the brain. Amphetamine-like drugs are substrates for monoamine transporters
, include NET, that cause a reversal in the direction of neurotransmitter transport. Amphetamines cause a large accumulation of extracellular NE. High levels of NE in the brain account for most of the profound effects of amphetamines, including alertness, anorectic, locomotor and sympathomimetic effects. However, the effects that amphetamines have on the brain are slower but last longer than the effects cocaine has on the brain. MDMA (3,4-Methylenedioxymethamphetamine or "ecstacy") is an amphetamine with wide recreational use. A study reported that the NET inhibitor Reboxetine
reduced the stimulant effects of MDMA in humans, demonstrating the crucial role NET has in the cardiovascular and stimulant-like effects of MDMA.
, affective disorder, and autonomic disorders. Recently discovered mechanisms of the NET, including the ability to act reversibly and as an ion channel, provide other areas of research.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the SLC6A2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
NET is a monoamine transporter
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
and is responsible for the Na+/Cl–-dependent reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
of extracellular norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE). NET can also reuptake extracellular dopamine
Dopamine
Dopamine 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...
(DA). The reuptake of these two neurotransmitters
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
is essential in regulating concentrations in the synaptic cleft. NETs, along with the other monoamine transporters, are the targets of many antidepressants and recreational drugs. In addition, a deficiency of NET is associated with many affective and autonomic disorders such as orthostatic intolerance
Orthostatic intolerance
Orthostatic intolerance is a subcategory of dysautonomia, a disorder of the autonomic nervous system occurring when an individual stands up....
and ADHD. There is evidence that single-nucleotide polymorphisms in the NET gene (SLC6A2) may be an underlying factor in some of these disorders.
Gene
The norepinephrine transporter gene, SLC6A2 is located on human chromosome 16 locus 16q12.2. This gene is encoded by 14 exonsExon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
. Based on the nucleotide and amino acid sequence, the NET transporter consists of 617 amino acids with 12 membrane-spanning domains. The structural organization of NET is highly homologous to other members of a sodium/chloride-dependent family of neurotransmitter transporters, including dopamine, epinephrine, 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...
and GABA transporters.
Single nucleotide polymorphisms
A single-nucleotide polymorphism (SNP) is a genetic variation in which a genome sequence is altered by a single nucleotide (AAdenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
, T
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
, C
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
or G
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
). NET proteins with an altered amino acid sequence (more specifically, a missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
) could potentially be associated with various diseases that involve abnormally high or low plasma levels of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
due to altered NET function. NET SNPs and possible associations with various diseases are an area of focus for many research projects. There is evidence suggesting a relationship between NET SNPs and various disorders such as ADHD psychiatric disorders, postural tachycardia
Postural orthostatic tachycardia syndrome
Postural orthostatic tachycardia syndrome is a condition of dysautonomia, more specifically orthostatic intolerance, in which a change from the supine position to an upright position causes an abnormally large increase in heart rate, called tachycardia...
and orthostatic intolerance
Orthostatic intolerance
Orthostatic intolerance is a subcategory of dysautonomia, a disorder of the autonomic nervous system occurring when an individual stands up....
. The SNPs rs3785143 and rs11568324 have been related to attention-deficit hyperactivity disorder
Attention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
. Thus far, however, the only confirmed direct association between a SNP and a clinical condition is that of the SNP, Ala457Pro, and orthostatic intolerance. Thirteen NET missense mutations have been discovered so far.
| Location | Amino Acid Variant | Related Disease |
|---|---|---|
| Exon 2 | Val69Ile | None |
| Exon 3 | Thr99Ile | None |
| Exon 5 | Val245Ile | None |
| Exon 6 | Asn292Thr | None |
| Exon 8 | Val356Leu | None |
| Exon 8 | Ala369Pro | None |
| Exon 8 | Asn375Ser | None |
| Exon 10 | Val449Ile | None |
| Exon 10 | Ala457Pro | Orthostatic intolerance Orthostatic intolerance Orthostatic intolerance is a subcategory of dysautonomia, a disorder of the autonomic nervous system occurring when an individual stands up.... |
| Exon 10 | Lys463Arg | None |
| Exon 11 | Gly478Ser | None |
| Exon 12 | Phe528Cys | None |
| Exon 13 | Tyr548His | None |
Genetic variations
An epigenetic mechanism (hypermethylation of CpG islands in the NET gene promoter region) that results in reduced expression of the noradrenaline transporter and consequently a phenotype of impaired neuronal reuptake of norepinephrine has been implicated in both postural orthostatic tachycardia syndromePostural orthostatic tachycardia syndrome
Postural orthostatic tachycardia syndrome is a condition of dysautonomia, more specifically orthostatic intolerance, in which a change from the supine position to an upright position causes an abnormally large increase in heart rate, called tachycardia...
and panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
.
Structure
The norepinephrine transporter is composed of 12 transmembrane domains (TMDs). The intracellular portion contains an aminoAmine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
(-) group and carboxyl
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
(-COOH) group. In addition, there is a large extracellular loop located between TMD 3 and 4. The protein is composed of 617 amino acids
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
.
Function
NET functions to transport synaptically released norepinephrineNorepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
back into the presynaptic neuron. As much as 90% of the norepinephrine released will be taken back up in the cell by NET. NET functions by coupling the influx of Na+ and Cl– with the transport of norepinephrine. This occurs at a fixed ratio of 1:1:1. Both NET and DAT
Dopamine transporter
The 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...
can transport norepinephrine and dopamine. The reuptake of norepinephrine and dopamine is essential in regulating the concentration of monoamine neurotransmitters in the synaptic cleft. The transporter also helps maintain homeostatic balances of the presynaptic neuron.
Norepinephrine (NE) is released from noradrenergic neurons that innervate both the CNS
Central 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...
and 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...
. NE, or noradrenaline (NA), has an important role in controlling mood, arousal, memory, learning, and pain perception. NE is a part of the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
. Dysregulation of the removal of norepinephrine by NET is associated with many neuropsychiatric diseases. In addition, any antidepressants and recreational drugs compete for the binding of NET with NE.
Transport mechanisms
The transport of norepinephrine back into presynaptic cell is made possible by the cotransport with Na&2B and Cl%2B. The sequential binding of the ions results in the eventual reuptake of norepinephrine. The ion gradients of Na%2B and Cl%2B make this reuptake energetically favorable. The gradient is generated by the Na%2B/K%2B-ATPase which transports three sodium ions out and two potassium ions into the cell. NETs have conductances similar to those of ligand gated ion channels. The expression of NET results in a leak-channel activity.Location in the nervous system
NETs are restricted to the noradrenergic neurons and are not present on neurons that release dopamine or epinephrine. The transporters can be found along the cell body, axonsAxon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
, and dendrites
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
of the neuron. NETs are located away from the synapse, where norepinephrine is released, closer to the plasma membrane of the cell. This requires norepinephrine to diffuse from the site it is released to the transporter for reuptake. Norepinephrine transporters are confined to the nerves of the sympathetic system, and those innervating the adrenal medulla, lung, and placenta.
Regulation
Regulation of NET function is complex and a focus of current research. NETs are regulated at both the cellular and molecular level post-translation. The most understood mechanisms include phosphorylation by the second messenger protein kinase CProtein 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...
(PKC). PKC has been shown to inhibit NET function by sequestration of the transporter from the plasma membrane. The amino acid sequence of NET has shown multiple sites related to protein kinase phosphorylation. Post-translational modifications can have a wide range of effects on the function of the NET, including the rate of fusion of NET-containing vesicles with the plasma membrane, and transporter turnover.
Orthostatic intolerance
Orthostatic intolerance (OI) is a disorder of the autonomic nervous systemAutonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
(a subcategory of dysautonomia
Dysautonomia
Dysautonomia is a broad term that describes any disease or malfunction of the autonomic nervous system. This includes postural orthostatic tachycardia syndrome , inappropriate sinus tachycardia , vasovagal syncope, mitral valve prolapse dysautonomia, pure autonomic failure, neurocardiogenic...
) characterized by the onset of symptoms upon standing. Symptoms include fatigue, lightheadedness, headache, weakness, increased heart rate/heart palpitations, anxiety, and altered vision. Oftentimes, patients have high plasma norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE) concentrations (at least 600 pg/ml) in relation to sympathetic outflow upon standing, suggesting OI is a hyperadrenergic
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
condition.
The discovery of identical twin sisters both suffering from OI suggested a genetic basis for the disorder. A missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
on the NET gene (SLC62A) was discovered in which an alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
residue was replaced with a proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
residue (Ala457Pro) in a highly conserved region of the transporter. The patients’ defective NET had only 2% of the activity of the wild-type
Wild type
Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
version of the gene. The genetic defect in the NET protein results in decreased NET activity that could account for abnormally high NE plasma levels in OI. However, 40 other OI patients did not have the same missense mutation, indicating other factors contributed to the phenotype in the identical twins. This discovery of the linkage with NET mutations that results in decreased norepinephrine reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
activity and orthostatic intolerance suggests faulty NE uptake mechanisms can contribute to cardiovascular disease.
Therapeutic uses
"The involvement of the norepinephrine transporter (NET) in the pathophysiologyPathophysiologyPathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
and treatment of attention deficit hyperactivity disorder (ADHD), substance abuseSubstance abuseA substance-related disorder is an umbrella term used to describe several different conditions associated with several different substances .A substance related disorder is a condition in which an individual uses or abuses a...
, neurodegenerative disorders (e.g., Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD) and Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
(PD)) and clinical depressionClinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
has long been recognized. [2006]"
Depression
Certain antidepressantAntidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
medications act to raise noradrenaline, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors
Norepinephrine-dopamine reuptake inhibitor
A norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
(NDRIs), norepinephrine reuptake inhibitors
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
(NRIs or NERIs) and the tricyclic antidepressants (TCAs). These medications prevent NET from functioning normally, resulting in higher extracellular concentrations of NE. Noradrenaline therefore remains in the synapse longer, allowing it to reach more normal levels. Since the noradrenaline transporter is responsible for most of the dopamine clearance in the prefrontal cortex, SNRIs would also raise dopamine levels in synapses there. However, dopamine in most brain regions is cleared primarily by the dopamine transporter
Dopamine transporter
The 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...
, which works roughly ten times faster.
For many years, the number one choice in treating mood disorders like depression was through the uptake of TCAs, such as 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...
(Norpramin), nortriptyline
Nortriptyline
Nortriptyline is a second-generation tricyclic antidepressant marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis...
(Arentyl, Pamelor), protriptyline (Vivactil) and amoxapine
Amoxapine
Amoxapine is a tetracyclic antidepressant of the dibenzoxazepine family, though it is often classified as a secondary amine tricyclic antidepressant.- Uses :...
(Asendin). However, currently far more potent drugs have been developed in the US, most notably the discovery of selective serotonin reuptake inhibitors (SSRIs). SSRIs affect the communication between chemical messengers in the brain by regulating how much of a certain chemical messenger enters the brain. SSRIs regulate serotonin levels in the brain, which seems to aid the brain in exchanging messages more efficiently and in turn livens mood. Drugs 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...
and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
are both very impelling in treating mood disorders because they reduce many of the side effects one receives compared to using TCAs to treat such mood disorders.
ADHD
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, Metadate, Concerta, Daytrana
Daytrana
Daytrana is a medicinal patch marketed by Shire Pharmaceuticals and developed under contract by Noven Pharmaceuticals that was approved in June 2007. In the literature, Daytrana is most commonly referred to as Methylphenidate Transdermal System .Daytrana is approved by the U.S...
), Amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
(Adderall
Adderall
Adderall is a brand name of amphetamine salts–based medication used for attention-deficit hyperactivity disorder and narcolepsy. It is a brand-name psychostimulant medication composed of racemic amphetamine aspartate monohydrate, racemic amphetamine sulfate, dextroamphetamine saccharide, and...
) and Dextroamphetamine
Dextroamphetamine
Dextroamphetamine is a psychostimulant drug which is known to produce increased wakefulness and focus as well as decreased fatigue and decreased appetite....
(Dexadrine, Detrostat).
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...
has not been fully understood, but has stimulated research into this topic. The only relationship that has been understood between researchers is that there is a positive correlation between increased NE levels in the brain and activity of schizophrenia. Before the age of modern treatment of schizophrenia, patients that were mentally ill were not treated and instead that were hidden away in their homes. Old treatments often included sedatives, electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...
(ECT), artificially induced comas and frontal lobotomies. Unfortunately, the side effects of these treatments usually outweighed the therapeutic benefits of these treatments. The first breakthrough for schizophrenia treatment was the discovery of the antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
drug called Chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
(CPZ) in 1979, which is still in common use today. Another drug developed from the class of atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
drug called Clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
. This drug works to help patients who have tried to injure/kill themselves before from getting no prior treatment. It works similarly to SSRIs by regulating the concentrations of certain chemical messengers in the brain.
Cocaine
CocaineCocaine
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...
is a powerful psychostimulant and known to be one of the most widely abused substances. Cocaine is a nonselective, competitive antagonist
Competitive antagonist
A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...
of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, 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...
, and dopamine
Dopamine
Dopamine 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...
transport. This thwarts the absorption of these chemicals into the presynaptic terminal and allows a large concentration of dopamine, serotonin and norepinephrine to build up in the cell. The potential for cocaine addiction is thought to be a result of its effects on dopamine transporters
Dopamine transporter
The 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...
in the CNS, while it has been suggested that the life-threatening cardiovascular effects of cocaine may involve the inhibition of NETs at sympathetic and CNS autonomic synapses.
Amphetamines
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
levels compared to that of 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...
in that they both increase NE levels in the brain. Amphetamine-like drugs are substrates for monoamine transporters
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
, include NET, that cause a reversal in the direction of neurotransmitter transport. Amphetamines cause a large accumulation of extracellular NE. High levels of NE in the brain account for most of the profound effects of amphetamines, including alertness, anorectic, locomotor and sympathomimetic effects. However, the effects that amphetamines have on the brain are slower but last longer than the effects cocaine has on the brain. MDMA (3,4-Methylenedioxymethamphetamine or "ecstacy") is an amphetamine with wide recreational use. A study reported that the NET inhibitor Reboxetine
Reboxetine
Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia . Its mesylate salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra...
reduced the stimulant effects of MDMA in humans, demonstrating the crucial role NET has in the cardiovascular and stimulant-like effects of MDMA.
Further research
NETs role in many brain disorders underlies the importance of understanding the (dys)regulation of the transporter. A complete model of the proteins that associate with the transporter will be useful in designing drug therapies for diseases such as schizophreniaSchizophrenia
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...
, affective disorder, and autonomic disorders. Recently discovered mechanisms of the NET, including the ability to act reversibly and as an ion channel, provide other areas of research.
See also
- Neurotransmitter transporterNeurotransmitter transporterNeurotransmitter 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...
- Sodium:neurotransmitter symporterSodium:neurotransmitter symporterSodium:neurotransmitter symporters is a family of neurotransmitter transporters.Neurotransmitter transport systems are responsible for the release, re-uptake and recycling of neurotransmitters at synapses....
- Solute carrier familySolute carrier familyThe solute carrier group of membrane transport proteins include over 300 members organized into 51 families. The SLC gene nomenclature system was originally proposed by the Human Genome Organization and is the basis for the official HUGO names of the genes that encode these transporters...
- NorepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
- Monoamine transporterMonoamine transporterMonoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
- Orthostatic intoleranceOrthostatic intoleranceOrthostatic intolerance is a subcategory of dysautonomia, a disorder of the autonomic nervous system occurring when an individual stands up....
- Single-nucleotide polymorphisms