Noradrenaline transporter

Noradrenaline transporter (NAT, SLC6A2), also called norepinephrine transporter (NET), belongs to the family of Na⁺/Cl^- dependent neurotransmitter transporters. Monoamine transporter subfamily consists of NAT, dopamine transporter (DAT, SLC6A3), and serotonin transporter (SERT, SLC6A4). Catecholamines adrenaline, noradrenaline, and dopamine are the endogenous substrates for both NAT and DAT; both transport also methamphetamine and amphetamine. NAT has even higher affinity towards dopamine than noradrenaline (Gu et al., 1994). The endogenous substrate of SERT is indolamine serotonin (5-HT). These three monoamine transporters are inhibited by cocaine. NAT inhibitors (NRIs) and SERT/NAT dual inhibitors (SNRIs), which do not inhibit DAT, have no significant potential for addiction, and are used in treatment of ADHD, OCD, depression, anxiety, panic disorder, and obesity.

Adrenergic system consists of the organs and nerves in which adrenaline or noradrenaline act as neurotransmitter or neurohormone. Adrenaline and noradrenaline are released as neurotransmitters from sympathetic nerve endings and as neurohormones from adrenal medulla.

NATs and DATs on presynaptic neurons rapidly sequester catecholamines that have been released into synapses, allowing their recycling. NAT is the primary determinant of synaptic noradrenaline concentration, accounting for ∼80-90% of the removal of norepinephrine. The number of NATs on cell surface is tightly controlled via by endocytic trafficking. Most of NATs are found in the cytoplasm, unlike DAT and SERT which are mostly located on plasma membrane.

NATs are found in the brain (noradrenergic neurons, non-adrenergic neural somata, axons, dendrites), peripheral sympathetic neurons, cromaffin cells of the adrenal medulla, and placenta. Tumours that have neuroendocrine origin express NAT, and can be detected using PET radiopharmaceuticals for NAT. NAT radiopharmaceuticals have also been used to detect brown adipose tissue depots.

NAT is involved in the pathophysiology and treatment of depression, attention-deficit hyperactivity disorder (ADHD), substance abuse, anorexia nervosa, hypertension and orthostatic intolerance, cardiovascular diseases, and neurodegenerative diseases, including AD and PD. NAT availability is markedly increased in major depressive disorder (Moriguchi et al., 2017). No significant differences in brain NAT availability were found between non-depressed obese and non-obese individuals (Hesse et al., 2017), but there may be a different NA modulated stress response in healthy obese and non-obese individuals (Schinke et al., 2019).

NAT can be used as a marker of presynaptic sympathetic nervous system activity and cardiac sympathetic innervation.

Metaraminol is a synthetic noradrenaline analogue that shares the same neuronal uptake, storage, and release pathways, but is not metabolized by COMT and MAO. Numerous ¹¹C and ¹⁸F labelled metaraminol and reboxetine derivatives have been developed, including [4-¹⁸F]FMR (Eskola et al., 2004), (S,S)-[¹¹C]MRB ([¹¹C]MeNER) (Wilson et al., 2003; Gallezot et al., 2011), and (S,S)-[¹⁸F]FMeNER-D₂ (Schou et al., 2004; Arakawa et al., 2008; Sekine et al., 2010; Moriguchi et al., 2017). [¹¹C]MRB has been used in many human brain studies, for instance in patients with Parkinson's disease (Sommerauer et al., 2018; Brumberg et al., 2019).

[^131/123I]MIGB is a benzylguanidine-based ligand which has been used for imaging of neuroendocrine tumours and sympathetic function in cardiac studies. Substituting ¹⁸F for iodine provides [¹⁸F]MFBG (Zhang et al., 2014a and 2014b), which has significantly better tumour detection rate than with [¹²³I]MIGB scintigraphy (Pauwels et al., 2023).

[¹⁸F]3F-PHPG and [¹⁸F]4F-MHPG (Kobayashi et al., 2017) are close analogues, too.

[¹¹C]NS8880 has high affinity and selectivity towards NAT, with faster kinetics than [¹¹C]MeNER in pig and rat (Vase et al., 2014). Its fluorine-18 labelled analogue [¹⁸F]NS12137 has been shown to be a promising radiotracer for NET imaging in the brain in preclinical studies (Kirjavainen et al., 2018; López-Picón et al., 2019).

[¹⁸F]LMI1195 (Higuchi et al., 2013; Sinusas et al., 2014; Werner et al., 2015) is promising for assessing myocardial sympathetic activity; similarly to noradrenaline and a widely used SPECT radiopharmaceutical [^131/123I]MIBG, [¹⁸F]LMI1195 is stored in vesicles and released after cell membrane depolarization, and is not metabolized by MAO (Werner et al., 2015; Chen et al., 2018). The mechanism of myocardial [¹⁸F]LMI1195 uptake may be species-dependent (Mu et al., 2020).

[¹⁸F]fluorodopamine is taken up into sympathetic nerves by NAT, converted by β-hydroxylase into [¹⁸F]fluoronoradrenaline, stored in the transmitter vesicles and released like noradrenaline; therefore the washout rate of activity from tissue is quantitatively related to the sympathetic activity (Grassi & Esler, 1999).

[¹¹C]HED is a widely used NAT radiopharmaceutical, based on sympathomimetic drug norfenefrine. It is transported by NAT, and suitable for measuring cardiac sympathetic innervation, because its retention in tissue is mainly determined by the tissue density of NAT, but partially also by intravesicular uptake (Grassi & Esler, 1999; Nomura et al., 2006).

See also:

• [¹⁸F]MFBG
• [¹⁸F]NS12137
• Adrenergic system
• Dopaminergic system
• Serotonergic system
• Cholinergic system
• Histamine

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Literature

Kristensen AS, Andersen J, Jørgensen TN, Sørensen L, Eriksen J, Loland CJ, Strømgaard K, Gether U. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev. 2011; 63(3):585-640. doi: 10.1124/pr.108.000869.

Logan J, Ding YS, Lin KS, Pareto D, Fowler J, Biegon A. Modeling and analysis of PET studies with norepinephrine transporter ligands: the search for a reference region. Nucl Med Biol. 2005; 32(5): 531-542. doi: 10.1016/j.nucmedbio.2005.04.005.

Pramod AB, Foster J, Carvelli L, Henry LK. SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol Aspects Med. 2013; 34(2-3): 197-219. doi: 10.1016/j.mam.2012.07.002.

Vuorenpää A: Cellular regulation of the norepinephrine transporter. Annales Universitatis Turkuensis, D1336. Sarja - ser. D osa - tom. 1336 ISBN: 978-951-29-7131-2.

Tags: Adrenaline, Noradrenaline, Dopamine, Catecholamines, NAT, Autonomic nervous system

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Updated at: 2023-02-06
Created at: 2017-10-07
Written by: Vesa Oikonen