Norepinephrine transporter

Source: Wikipedia, the free encyclopedia.

SLC6A2
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000103546

ENSMUSG00000055368

UniProt

P23975

O55192

RefSeq (mRNA)

NM_001043
NM_001172501
NM_001172502
NM_001172504

NM_009209

RefSeq (protein)

NP_001034
NP_001165972
NP_001165973
NP_001165975

NP_033235

Location (UCSC)Chr 16: 55.66 – 55.71 MbChr 8: 93.69 – 93.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

NET is a

single-nucleotide polymorphisms in the NET gene (SLC6A2) may be an underlying factor in some of these disorders.[7]

Gene

The norepinephrine transporter gene, SLC6A2 is located on human

GABA transporters.[7]

Single-nucleotide polymorphisms

A

attention-deficit hyperactivity disorder.[10] Thus far, however, the only confirmed direct association between a SNP and a clinical condition is that of the SNP, Ala457Pro, and orthostatic intolerance.[7] Thirteen NET missense mutations have been discovered so far.[7]

Missense Mutations in the NET Gene[7][11]
Location Amino Acid Variant TMD (if known) Related Disease
Exon 2 Val69Ile TMD 1 None
Exon 3 Thr99Ile TMD 2 None
Exon 5 Val245Ile TMD 4 None
Exon 6 Asn292Thr n/a None
Exon 8 Val356Leu n/a None
Exon 8 Ala369Pro n/a None
Exon 8 Asn375Ser n/a None
Exon 10 Val449Ile TMD 9 None
Exon 10 Ala457Pro TMD 9 Orthostatic intolerance
Exon 10 Lys463Arg n/a None
Exon 11 Gly478Ser TMD 10 None
Exon 12 Phe528Cys n/a None
Exon 13 Tyr548His n/a None
Abbreviations: TMD, transmembrane domain; n/a, non-applicable.
For the table above, refer to this table of standard amino acid abbreviations. This notation for
missense mutations, take Val69Ile for example, indicates that amino acid Val69 was changed to Ile.

Genetic variations

An

epigenetic mechanism (hypermethylation of CpG islands in the NET gene promoter region) that results in reduced expression of the noradrenaline (norepinephrine) transporter and consequently a phenotype of impaired neuronal reuptake of norepinephrine has been implicated in both postural orthostatic tachycardia syndrome and panic disorder.[12]

rs5569 is a variant of SLC6A2.[13]

Structure

Simplified structure of the norepinephrine transporter protein.

The norepinephrine transporter is composed of 12 transmembrane domains (TMDs). The intracellular portion contains an amino (-NH
2) group and carboxyl (-COOH) group. In addition, there is a large extracellular loop located between TMD 3 and 4.[14][6][15] The protein is composed of 617 amino acids.[14]

Function

NET functions to transport synaptically released norepinephrine 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 sodium and chloride (Na+/Cl−) with the transport of norepinephrine. This occurs at a fixed ratio of 1:1:1.[16] Both the NET and the dopamine transporter (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.[17]

Norepinephrine structure

Norepinephrine (NE) is released from noradrenergic neurons that innervate both the CNS and PNS. NE, also known as noradrenaline (NA), has an important role in controlling mood, arousal, memory, learning, and pain perception. NE is a part of the sympathetic nervous system.[6][18] Dysregulation of the removal of norepinephrine by NET is associated with many neuropsychiatric diseases, discussed below. In addition, many antidepressants and recreational drugs compete for the binding of NET with NE.[14]

Transport mechanisms

The transport of norepinephrine back into presynaptic cell is made possible by the cotransport with Na+ and Cl−. The sequential binding of the ions results in the eventual reuptake of norepinephrine. The ion gradients of Na+ and Cl− make this reuptake energetically favorable. The gradient is generated by the

Na+/K+-ATPase which transports three sodium ions out and two potassium ions into the cell.[17] NETs have conductances similar to those of ligand-gated ion channels. The expression of NET results in a leak-channel activity.[16][17]

Location in the nervous system

NETs are restricted to noradrenergic neurons and are not present on neurons that release dopamine or epinephrine.[6][15][17] The transporters can be found along the cell body, axons, and dendrites of the neuron.[6] NETs are located away from the synapse, where norepinephrine is released. They are found closer to the plasma membrane of the cell. This requires norepinephrine to diffuse from the site it is released to the transporter for reuptake.[17] Norepinephrine transporters are confined to the neurons of the sympathetic system, and those innervating the adrenal medulla, lung, and placenta.[17]

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 C (PKC).[15] PKC has been shown to inhibit NET function by sequestration of the transporter from the plasma membrane.[19] The amino acid sequence of NET has shown multiple sites related to protein kinase phosphorylation.[17] 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.[19]

Clinical significance

Orthostatic intolerance

Main article: Orthostatic intolerance

Orthostatic intolerance (OI) is a disorder of the

heart palpitations, anxiety, and altered vision.[7] Often, 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.[7][9]
The discovery of identical twin sisters who both had OI suggested a genetic basis for the disorder.[7][9] A missense mutation on the NET gene (SLC6A2) was discovered in which an alanine residue was replaced with a proline residue (Ala457Pro) in a highly conserved region of the transporter.[7] The patients’ defective NET had only 2% of the activity of the wild-type version of the gene.[7] 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.[7] 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.[20]

Therapeutic uses

Inhibition of the norepinephrine transporter (NET) has potential therapeutic applications in the treatment of

clinical depression.[18]

Major depressive disorder

Main article: Major depressive disorder
NDRI tricyclic antidepressant
Fluoxetine, a selective serotonin reuptake inhibitor

Certain

5-HT are maintained in the synapse increasing the concentrations of the latter neurotransmitters. Since the noradrenaline transporter is responsible for most of the dopamine clearance in the prefrontal cortex,[21] SNRIs block reuptake of dopamine too, accumulating the dopamine in the synapse. However, DAT, the primary way dopamine is transported out of the cell, can work to decrease dopamine concentration in the synapse when the NET is blocked.[22] For many years, the number one choice in treating mood disorders like depression was through administration of TCAs, such as desipramine (Norpramin), nortriptyline (Arentyl, Pamelor), protriptyline (Vivactil), and amoxapine (Asendin).[18] SSRIs, which mainly regulate serotonin, subsequently replaced tricyclics as the primary treatment option for depression because of their better tolerability and lower incidence of adverse effects.[23]

ADHD

Main article:
ADHD
Atomoxetine, an NET inhibitor marketed as Strattera

Many drugs exist in the treatment of ADHD.

neurotransmitters in the brain. The strong selective norepinephrine reuptake inhibitor (NRI), atomoxetine (Strattera), has been approved by the U.S. Food and Drug Administration (FDA) to treat ADHD in adults.[24][25] The role of the NET in ADHD is similar to how it works to ease the symptoms of depression. The NET is blockaded by atomoxetine and increases NE levels in the brain. It can work to increase one's ability to focus, decrease any impulsiveness, and lessen hyperactivity in both children and adults with ADHD.[26]

Psychostimulants

Cocaine

Main article: Cocaine

presynaptic terminal[27] and allows a large concentration of dopamine, serotonin and norepinephrine to build up in the synaptic cleft. 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.[28]

Amphetamines

Main article: Amphetamine
The chemical structure of MDMA or "ecstasy"

Amphetamines have an effect on norepinephrine levels similar to that of cocaine in that they both increase NE levels in the brain.[29] Amphetamine-like drugs are substrates for monoamine transporters, include NET, that cause a reversal in the direction of neurotransmitter transport.[17][30] Amphetamines cause a large accumulation of extracellular NE.[29] High levels of NE in the brain account for most of the profound effects of amphetamines, including alertness and anorectic, locomotor and sympathomimetic effects.[29] However, the effects that amphetamines have on the brain are slower but last longer than the effects cocaine has on the brain.[29] MDMA (3,4-Methylenedioxymethamphetamine or "ecstasy") 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.[31]

Further research

The role of the NET 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

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.[15][17]

Schizophrenia

Main article: Schizophrenia
3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of NE
. Abnormally high levels of MHPG are also indicative of impaired NE regulation.

The role of NE in

MHPG (3-methoxy-4-hydroxyphenylglycol), a metabolite of NE, in the normal control group, but not in the group of schizophrenic patients.[34] This suggests that in schizophrenia, the alpha-2 adrenergic receptor, a presynaptic inhibitory receptor, may be less sensitive compared to normally functioning alpha-2 receptors and thus relate to elevated NE levels in the disorder.[34] In addition to increased NE levels in the brain and CSF, increased levels of MHPG has also been associated with a diagnosis of schizophrenia.[35] Impaired NE regulation in schizophrenia has been an area of interest for researchers and research on this topic is still ongoing.[34][35]

Imaging

Via

radio tracers for PET imaging.[36] Fluorescent substrates for the transporter can also be used to monitor the transporter rate in isolated organs or tissues,[37][38]
although these are not suitable for clinical imaging.

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000103546 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055368 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  13. ^ dbSNP
  14. ^
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  15. ^
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  23. ^ Clinical Pharmacology of SSRI's: How SSRIs as a Group Differ From TCAs, Preskorn
  24. ^ "What medications are used to treat ADHD?". National Institutes of Mental Health.
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  26. ^ "Atomoxetine -". PubMed Health. Retrieved 2 November 2011.
  27. ^
    PMID 12514195
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  29. ^ a b c d Drug and Human Performance Fact Sheets. "Methamphetamine (And Amphetamine)". Archived from the original on 31 October 2011. Retrieved 1 November 2011.
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  32. ^ a b Decaire M. "The neurophysiology of schizophrenia: Etiology and Psychopharmacological treatment". Archived from the original on 17 February 2012. Retrieved 1 November 2011.
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    PMID 2221157
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External links
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