The
norepinephrine transporter or
NET (or noradrenaline transporter (NAT)) is a
monoamine transporterMonoamine transporters are structures in nerve-cell membranes that function as neurotransmitter transporters transferring monoamine neurotransmitters in or out of cells.-Types:There are several different monoamine transporters:*The dopamine transporter, DAT....
that transports the
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
norepinephrineNoradrenaline or norepinephrine is a catecholamine with dual roles as a hormone and a neurotransmitter....
(noradrenaline) from the synapse back to its
vesiclesIn a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
for storage until later use. It also appears to transport the neurotransmitter
dopamineDopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D
1, D
2, D
3, D
4, and...
in the same way, but to a lesser degree. "The norepinephrine transporter (NET) protein consists of 617 amino acids and has 12 transmembrane domains" and is encoded by the
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
.
Certain
antidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors , tricyclic antidepressants , tetracyclic antidepressants , selective serotonin reuptake inhibitors , and serotonin-norepinephrine...
medications act to raise noradrenaline, such as the
SNRISNRI may refer to:* Serotonin-norepinephrine reuptake inhibitor* Strategic Naval Research Institute...
s and the tricyclic antidepressants (TCAs).
The
norepinephrine transporter or
NET (or noradrenaline transporter (NAT)) is a
monoamine transporterMonoamine transporters are structures in nerve-cell membranes that function as neurotransmitter transporters transferring monoamine neurotransmitters in or out of cells.-Types:There are several different monoamine transporters:*The dopamine transporter, DAT....
that transports the
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
norepinephrineNoradrenaline or norepinephrine is a catecholamine with dual roles as a hormone and a neurotransmitter....
(noradrenaline) from the synapse back to its
vesiclesIn a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
for storage until later use. It also appears to transport the neurotransmitter
dopamineDopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D
1, D
2, D
3, D
4, and...
in the same way, but to a lesser degree. "The norepinephrine transporter (NET) protein consists of 617 amino acids and has 12 transmembrane domains" and is encoded by the
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
.
Certain
antidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors , tricyclic antidepressants , tetracyclic antidepressants , selective serotonin reuptake inhibitors , and serotonin-norepinephrine...
medications act to raise noradrenaline, such as the
SNRISNRI may refer to:* Serotonin-norepinephrine reuptake inhibitor* Strategic Naval Research Institute...
s and the tricyclic antidepressants (TCAs). In other words, these medications prevent the noradrenaline transporter from doing its job. Noradrenaline therefore remains in the synapse longer, allowing it to reach more normal levels. Since the noradrenaline transporter is also thought to transport dopamine to some extent, SNRIs would also raise dopamine levels in the synapse.
"The involvement of the norepinephrine transporter (NET) in the pathophysiologyPathophysiology 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 abuseAlthough the term substance can refer to any physical matter, substance abuse has come to refer to the overindulgence in and dependence of a drug or other chemical leading to effects that are detrimental to the individual's physical and mental health, or the welfare of others.]The disorder is...
, neurodegenerative disorders (e.g., Alzheimer's diseaseAlzheimer's disease , also called Alzheimer disease, Senile Dementia of the Alzheimer Type or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was...
(AD) and Parkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions....
(PD)) and clinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities...
has long been recognized. [2006]"
Genetics
The norepinephrine transporter is coded by a gene called "solute carrier family 6, member 2" with the gene symbol
SLC6A2.
In humans it is located on chromosome 16 locus 16q12.2.
There are several variations in the gene,
e.g., these
single nucleotide polymorphismA single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C, or G — in the genome differs between members of a species...
(SNP):
- T-182C (rs2242446), a promoter
In genetics, a promoter is a region of DNA that facilitates the transcription of a particular gene. Promoters are typically located near the genes they regulate, on the same strand and upstream .-Overview:...
variant
- A1287G (rs5569
In genetics, rs5569 is a genetic variant.It is a single nucleotide polymorphism in the SLC6A2 gene in exon 9.This gene codes the norepinephrine transporter.The SNP is a silent substitution and...
)
- A-3081T in the promoter region
- Ala457Pro (C1369G) in exon 9
- rs3785143
- rs11568324
The Ala457Pro rare
missense mutationIn 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...
results in a loss of function and has been associated with
orthostatic intoleranceOrthostatic intolerance is a subcategory of dysautonomia, a disorder of the autonomic nervous system occurring when an individual stands up....
(associated with
postural orthostatic tachycardia syndromePostural orthostatic tachycardia syndrome is a condition of dysautonomia, and 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...
) in one kindred.
Orthostatic intolerance is, however, not typically associated with the mutation.
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 noradrenaline has been implicated in both postural orthostatic tachycardia syndrome and
panic disorderPanic 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...
.
The SNPs rs3785143 and rs11568324 have been related to the
attention-deficit hyperactivity disorderAttention-deficit hyperactivity disorder is a neurobehavioral developmental disorder. ADHD is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone." While symptoms may appear to be innocent and merely annoying...
.
See also
- Neurotransmitter transporter
Neurotransmitter transporters are a class of membrane transport proteins that span cellular membranes and that serve to carry neurotransmitters across these membranes and to transport them to specific locations. There are more than twenty types of neurotransmitter transporters...
- Sodium:neurotransmitter symporter
Sodium:neurotransmitter symporters is a family ofneurotransmitter transporters.Neurotransmitter transport systems are responsible for the release, re-uptake and recycling of neurotransmitters at synapses....
- Solute carrier family
The SoLute Carrier group of membrane transport proteins include over 300 members organized into 47 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...
External links