Extraneuronal transporter

Horn, A.S., Characteristics of transport in dopamine neurons, in The Mechanism of Neuronal and Extraneuronal Transport of Catecholamines, Paton, D.M., Ed., Raven Press, New York, 195, 1976. 

Three extraneuronal transporters handle a range of endogenous and exogenous substrates see Table 6 ). ENT, the extraneuronal amine transporter uptake 2 or OCT3), is an organic cation transporter. Relative to NET, ENT exhibits lower affinity for catecholamines, favors Epi over NE or DA, and shows a higher maximal rate of catecholamine uptake. ENT is not Na -dependent and... 

ABBREVIATIONS NET, norepinephrine transporter, originally known as uptake 1 DAT, dopamine transporter ENT (OCT3), extraneuronal transporter, originally known as uptake 2 OCTl, OCT2, organic cation transporters Epi, epinephrine NE, norepinephrine DA, dopamine. 

Substrate specificity is determined by high affinity for the cognate neurotransmitter substrate. However, low affinity uptake does also have a part in the clearance of transmitters from the interstitial space (e.g., in uptake mediated by the extraneuronal monoamine transporter, EMT) and in the intestinal absoiption of glycine and glutamate. It is obvious that there is an evolutionary relation of neurotransmitter transporters and amino acid and cation transporters in epithelia. 

Figure 20.1 Schematic diagram illustrating how antidepressants increase the concentration of extraneuronal neurotransmitter (noradrenaline and/or 5-HT). In the absence of drug (b), monoamine oxidase on the outer membrane of mitochondria metabolises cytoplasmic neurotransmitter and limits its concentration. Also, transmitter released by exocytosis is sequestered from the extracellular space by the membrane-bound transporters which limit the concentration of extraneuronal transmitter. In the presence of a MAO inhibitor (a), the concentration of cytoplasmic transmitter increases, causing a secondary increase in the vesicular pool of transmitter (illustrated by the increase in the size of the vesicle core). As a consequence, exocytotic release of transmitter is increased. Blocking the inhibitory presynaptic autoreceptors would also increase transmitter release, as shown by the absence of this receptor in the figure. In the presence of a neuronal reuptake inhibitor (c), the membrane-bound transporter is inactivated and the clearance of transmitter from the synapse is diminished...

Figure 20.6 Schematic representation of the effects of 5-HT reuptake inhibitors on serotonergic neurons, (a) 5-HT is released at the somatodendritic level and by proximal segments of serotonergic axons within the Raphe nuclei and taken up by the 5-HT transporter. In these conditions there is little tonic activation of somatodendritic 5-HTia autoreceptors. At nerve terminals 5-HTib receptors control the 5-HT synthesis and release in a local manner, (b) The blockade of the 5-HT transporter at the level of the Raphe nuclei elevates the concentration of extraneuronal 5-HT to an extent that activates somatodendritic autoreceptors (5-HTia). This leads to neuronal hyperpolarisation, reduction of the discharge rate and reduction of 5-HT release by forebrain terminals, (c) The exposure to an enhanced extracellular 5-HT concentration produced by continuous treatment with SSRIs desensitises Raphe 5-HTia autoreceptors. The reduced 5-HTia function enables serotonergic neurons to recover cell firing and terminal release. Under these conditions, the SSRI-induced blockade of the 5-HT transporter in forebrain nerve terminals results in extracellular 5-HT increases larger than those observed after a single treatment with SSRIs. (Figure and legend taken from Hervas et al. 1999 with permission)...

Wu, X., et al. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J. Biol. Chem. 1998, 273, 32776-32786. 

Grundemann D, Schechinger B, Rap-pold GA, Schomig E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nature Neurosci 1998 1(5) 349 351. 

Wieiand A, Hayer-Zillgen M, Bonisch H, Bruss M. Analysis of the gene structure of the human (SLC22A3) and murine (Slc22a3) extraneuronal monoamine transporter. J Neural Transm 2000 107(10) 1149-1157. 

Active transport of the released transmitter into effector cells extraneuronal uptake) followed by enzymatic inactivation by catechol-O-methyltransferase. 

Catecholamines can be transported into effector cells extraneuronal uptake). These cells generally contain both COMT and MAO. The combined processes of extraneuronal uptake and 0-methylation are believed to be a minor but functionally significant, site of irreversible loss of catecholamines. The precise role of extraneuronal MAO in transmitter inactivation remains unknown. 

The action of norepinephrine is terminated by reuptake mechanisms, two of which have been identified. Biogenic amine Uptake 1 is located in the presynaptic membrane, requires energy for the transport, is sodium and temperature dependent, and is inhibited by ouabain (a cardiac glycoside), cocaine (a local anesthetic), and imipramine (an antidepressant). Biogenic amine Uptake 2 is located extraneuronally in various smooth muscles and glands, requires energy, and is temperature dependent. Approximately 20% of the amine is either taken up by the Uptake 2 mechanism or is metabolized. 

Lazar A, Grundemann D, Berkels R, Taubert D, Zimmermann T, Schomig E. Genetic variations of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet 2003 48 226-230. 

Zwart R, Verhaagh S, Buitelaar M, et al. Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol 2001 21 4188 4196. 

Mathews TA, Fedele DE, Coppelli FM, Avila AM, Murphy DL, Andrews AM. Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J Neurosci Methods 2004 140(1—2) 169—181. 

The histopathological characteristics of the brain in Alzheimer s diseases (AD) are the presence of intraneuronal neurofibrillary tangles (NFTs), extraneuronal amyloid-rich senile plaques, and a massive loss of neurons of the telencephalon. Although amyloid proteins are unique to senile plaques, several components are common to both senile plaques and NFTs hyperphosphory-lated tau proteins, ubiquitin, a 1-antichymotrypsin, apolipoprotein E, heparan sulfate proteoglycans, and Al and Fe [29]. Recent reports on Al and Fe transport mechanisms and the relation between them in AD are reviewed below. 

The effect of released norepinephrine wanes quickly, because -90% is transported back into the axoplasm by a specific transport mechanism (norepinephrine transporter, NAT) and then into storage vesicles by the vesicular transporter (neuronal reuptake). The NAT can be inhibited by tricyclic antidepressants and cocaine. Moreover, norepinephrine is taken up by transporters into the effector cells (extraneuronal monoamine transporter, EMT). Part of the norepinephrine undergoing reuptake is enzymatically inactivated to normetanephrine via catecholamine O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells) and to dihydroxymandelic acid via monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells). 

Donnan GA, Kaczmarczyk SJ, Paxinos G, Chilco PJ, Kalnins RM, Woodhouse DG, Mendelsohn FA (1991) Distribution of catecholamine uptake sites in human brain as determined by quantitative [3H] mazindol autoradiography. J Comp Neurol 304 419-434 Eisenhofer G (2(X)1) The role of neuronal tmd extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 91 35-62... 

Noradrenaline is transported by uptake systems that have been extensively studied. On release of noradrenaline from sympathetic nerve varicosities in the peripheral nervous system, it is subject to two uptake systems. Uptake 1 (UJ is a reuptake process where the noradrenaline is recovered by the nerve via a process that has a high affinity but relatively low maximum rate, whereas a second process, uptake 2 (Uj), clears noradrenaline from the tissues into extraneuronal sites by a low affinity, but fast, process (which is inhibited by GLUCOCORTICOIDS, phenoxybenzamine and normetanephrine). The first - the neuronal system - has been studied in detail, and is essentially the same process as used for dopamine and 5-hydroxytryptamine in the CNS. The U transport protein has now been cloned, and is one of a famiiy of transporter proteins which act as co-transporters for Na, Cl and the amine, driven by the ATP-generated electrochemical gradient for Na . This Ui noradrenaline reuptake process is inhibited by cocaine and amphetamine (thus accounting for some of their actions, particularly within the CNS), phenoxybenzamine and the extensive class of tricyclic and related compounds that are used as ANTIDEPRESSANTS (e.g. desipramine). 

The neuronal monoamme transporters provide the principal mechanism for rapid termmation of the signal in neuronal transmission, whereas the transporters at extraneuronal locations are more important for limiting the spread of the signal and for clearance of catecholamines from the bloodstream. For the norepinephrine released by sympathetic nerves, about 90% is removed back into nerves by neuronal uptake, 5% is removed by extraneuronal uptake, and 5% escapes these processes to enter the bloodstream. In contrast, for the epinephrine released directly into the bloodstream from the adrenals, about 90% is removed by extraneuronal monoamine transport processes that are particularly important in the liver. The presence of these highly active transport processes means that monoamines are rapidly cleared from the bloodstream with a circulatory half-life of less than 2 minutes. 

Eisenhofer G. The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 2001 91 35-62. 

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