The Transport of Amines Across the Axonal Membranes of Noradrenergic and Dopaminergic Neurones

Graefe, Karl Heinz; Bönisch, Heinz

doi:10.1007/978-3-642-46625-0_4

Cited by 87 publications

(60 citation statements)

References 127 publications

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“…These three amines are known substrates of SERT, and this ranking order is in perfect agreement with the ranking order of substrate affinity of SERT (serotonin Ͼ Ͼ dopamine Ն noradrenaline) (Eshleman et al, 1999;Miller et al, 2001). Moreover, it is clearly distinct from the ranking order of substrate affinity of two other neuronal monoamine transporters, the NAT, and the DAT (for both of them: dopamine Ͼ noradrenaline Ͼ Ͼ serotonin; for review, Graefe and Bönisch, 1988). Of worth noticing is the fact that the K m value of serotonin relative to SERTmediated transport (0.3-0.6 M;Blakely et al, 1991;Miller et al, 2001) is very similar to its IC 50 value (0.998 M) obtained in the present study (which should be very approximate to its k i value, because we used a substrate concentration below the K m value).…”

Section: Uptake Of Serotonin By Human Intestinal Caco-2 Cells 359supporting

confidence: 71%

Uptake of Serotonin at the Apical and Basolateral Membranes of Human Intestinal Epithelial (Caco-2) Cells Occurs through the Neuronal Serotonin Transporter (SERT)

Martel¹,

Monteiro²,

Lemos³

2003

J Pharmacol Exp Ther

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Serotonin plays important physiological functions at the intestinal level. However, nothing is known concerning its inactivation mechanisms in the human intestine. So, the aim of this work was to characterize the uptake of serotonin at the apical and basolateral membranes of human intestinal epithelial (Caco-2) cells. Uptake of [ 3 H]serotonin at the apical membrane of Caco-2 cells was specific and Na ϩ -, Cl Ϫ -, and potentialdependent. It was concentration dependently inhibited by several monoamines (with the following rank order of potency: serotonin Ͼ Ͼ dopamine Ն noradrenaline) and tricyclic and nontricyclic antidepressants (with the following rank order of potency: fluoxetine Ͼ desipramine Ͼ cocaine Ͼ GBR 12909). In contrast, it was not affected by corticosterone (0.01-100 M) and was only partially inhibited by decynium-22 (0.001-10 M). Transepithelial apparent permeability (P app ) to [ 3 H]serotonin in the apical-to-basolateral direction was reduced by desipramine (0.4 M) and fluoxetine (0.02 M), and it was not Na ϩ -dependent nor affected by corticosterone (100 M). Uptake of [3 H]serotonin at the basolateral membrane of Caco-2 cells was Na ϩ -dependent and reduced by desipramine (0.4 M) and fluoxetine (0.02 M), and it was not affected by corticosterone (100 M).The P app to [3 H]serotonin in the basolateral-to-apical direction was reduced by desipramine (0.4 M) and fluoxetine (0.02 M), and it was not affected by Na ϩ omission or by corticosterone (100 M). Reverse transcriptase-polymerase chain reaction indicates that mRNA of the neuronal serotonin transporter (SERT) is present in Caco-2 cells and in human small intestine. In conclusion, these results suggest that human intestinal epithelial Caco-2 cells functionally express SERT, both at their apical and basolateral cell membranes.The largest store of serotonin in the body is found in the gastrointestinal tract, corresponding to over 95% of the body's serotonin (Erspamer, 1966). Most of the gastrointestinal serotonin is contained in enterochromaffin (EC) cells of the mucosal epithelium, within which serotonin is synthesized from L-tryptophan and stored in secretory granules. Serotonin is also present in serotonergic neurons of the enteric nervous system. Several functions of enteric serotonin have been identified in the past years. First, serotonin acts as the neurotransmitter of a subset of myenteric interneurons (Wade et al., 1994). Second, serotonin contained in EC cells, being released in response to chemical or mechanical stimuli, affects gastrointestinal motility (it initiates peristaltic reflexes by acting on intrinsic sensory neurons and musculature) and intestinal electrolyte transport (it initiates secretory reflexes by acting on intrinsic sensory neurons and mucosal cells) (Engel et al., 1984;Imada-Shirakata et al., 1997). Moreover, extrinsic sensory neurons activated by serotonin initiate sensations from the bowel, which may include nausea, bloating, and pain (for review, see Gershon, 1999). Additionally, serotonin present in EC cells...

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Section: Uptake Of Serotonin By Human Intestinal Caco-2 Cells 359supporting

confidence: 71%

Uptake of Serotonin at the Apical and Basolateral Membranes of Human Intestinal Epithelial (Caco-2) Cells Occurs through the Neuronal Serotonin Transporter (SERT)

Martel¹,

Monteiro²,

Lemos³

2003

J Pharmacol Exp Ther

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“…Tricyclic antidepressants enhance noradrenergic transmission by binding to the norepinephrine transporter (NET), a plasma membrane protein responsible for terminating the action of norepinephrine in the noradrenergic synapse (Iversen, 1975;Graefe and Bonisch, 1988). Blockade of the NET by these drugs results in a prolongation of the action of norepinephrine in the synapse (Graefe and Bonisch, 1988;Barker and Blakely, 1995).…”

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confidence: 99%

“…Blockade of the NET by these drugs results in a prolongation of the action of norepinephrine in the synapse (Graefe and Bonisch, 1988;Barker and Blakely, 1995). Given the importance of the NET to noradrenergic transmission, it is conceivable that regulation of the level of expression of the NET gene in noradrenergic neurons may be a natural mechanism by which noradrenergic transmission can be adjusted in vivo in response to physiological demands placed on this system.…”

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confidence: 99%

Reduced Levels of Norepinephrine Transporters in the Locus Coeruleus in Major Depression

et al. 1997

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The norepinephrine transporter (NET) is a membrane protein responsible for termination of the action of synaptic norepinephrine and is a site of action of many drugs used to treat major depression. The present study determined whether the binding of [ 3 H]nisoxetine to the NET is altered in the locus coeruleus (LC) in major depression, using brain tissue collected postmortem from subjects diagnosed with major depression and from age-matched normal control subjects. Thirteen of the 15 major depressive subjects studied died by suicide. The distribution of [ 3 H]nisoxetine binding along the rostro-caudal axis of the nucleus was uneven and was paralleled by a similar uneven distribution of neuromelanin-containing cells in both major depressives and psychiatrically normal control subjects. The binding of [ 3 H]nisoxetine to NETs in the midcaudal portion of the LC from major depressive subjects was significantly lower than that from age-matched, normal control subjects. The binding of [ 3 H]nisoxetine to NETs in other regions of the LC was similar in major depressives and control subjects. In contrast to reductions in binding to NETs, there were no significant differences in the number of noradrenergic cells at any particular level of the LC between major depressives and normal control subjects. The decreased binding of [ 3 H]nisoxetine to NETs in the LC in major depression may reflect a compensatory downregulation of this transporter protein in response to an insufficient availability of its substrate (norepinephrine) at the synapse.

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“…A hallmark of aminergic neurons is their use of presynaptic transporters to clear released neurotransmitter (Iversen, 1967;Axelrod and Kopin, 1969;Graefe and Bönisch, 1988;Barker and Blakely, 1995). Dopamine (DA) and L-NE are cleared from extracellular spaces after vesicular release by specialized transporters localized in the plasma membrane of neuronal terminals, varicosities, and dendrites (von Euler, 1972;Trendelenburg, 1991;Boja et al, 1994;Ciliax et al, 1995;Nirenberg et al, 1996).…”

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Molecular Cloning and Characterization of anl-Epinephrine Transporter from Sympathetic Ganglia of the Bullfrog,Rana catesbiana

et al. 1997

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Chemical signaling by dopamine (DA) and L-norepinephrine (L-NE) at synapses is terminated by uptake via specialized presynaptic transport proteins encoded by the DA transporter (DAT) and L-NE transporter (NET) genes, respectively. In some vertebrate neurons, particularly the sympathetic neurons of amphibians, L-NE is converted to L-epinephrine (L-Epi, adrenaline) and released as the primary neurotransmitter. Although evidence exists for a molecularly distinct L-Epi transporter (ET) in the vertebrate brain and peripheral nervous system, a transporter specialized for extracellular L-Epi clearance has yet to be identified. To pursue this issue, we cloned transporter cDNAs from bullfrog (Rana catesbiana) paravertebral sympathetic ganglia and characterized functional properties via heterologous expression in non-neuronal cells. A cDNA of 2514 bp (f ET) was identified for which the cognate 3.1 kb mRNA is highly enriched in frog sympathetic ganglia. Sequence analysis of the f ET cDNA reveals an open reading frame coding for a protein of 630 amino acids. Inferred f ET protein sequence bears 75, 66, and 48% amino acid identity with human NET, DAT, and the 5-hydroxytryptamine transporter (SERT), respectively. Transfection of f ET confers Na ϩ -and Cl Ϫ -dependent catecholamine uptake in HeLa cells. Uptake of [ 3 H]-L-NE by f ET is inhibited by catecholamines in a stereospecific manner. L-Epi and DA inhibit f ET-mediated [3 H]-L-NE uptake more potently than they inhibit [ 3 H]-L-NE uptake by human NET (hNET), whereas L-NE exhibits equivalent potency between the two carriers. Moreover, f ET exhibits a greater maximal velocity (V max ) for the terminal products of catecholamine biosynthesis (L-Epi Ͼ L-NE Ͼ Ͼ DA), unlike hNET, in which a V max rank order of L-NE Ͼ DA Ͼ L-Epi is observed. f ET-mediated transport of catecholamines is sensitive to cocaine and tricyclic antidepressants, with antagonist potencies significantly correlated with hNET inhibitor sensitivity. Amino acid conservation and divergence of f ET with mammalian catecholamine transporters help define residues likely to be involved in catecholamine recognition and translocation as well as blockade by selective reuptake inhibitors.

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The Transport of Amines Across the Axonal Membranes of Noradrenergic and Dopaminergic Neurones

Cited by 87 publications

References 127 publications

Uptake of Serotonin at the Apical and Basolateral Membranes of Human Intestinal Epithelial (Caco-2) Cells Occurs through the Neuronal Serotonin Transporter (SERT)

Uptake of Serotonin at the Apical and Basolateral Membranes of Human Intestinal Epithelial (Caco-2) Cells Occurs through the Neuronal Serotonin Transporter (SERT)

Reduced Levels of Norepinephrine Transporters in the Locus Coeruleus in Major Depression

Molecular Cloning and Characterization of anl-Epinephrine Transporter from Sympathetic Ganglia of the Bullfrog,Rana catesbiana

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