5-Hydroxytryptamine transporters

HTTLPR = 5-hydroxytryptamine transporter long promoter region. a... 

Synaptic serotonin (5-hydroxytryptamine) transporters are inhibited by amphetamines, the tropane alkaloids cocaine and ecgonine [194] and by the indole alkaloid ibogaine (12-methoxyibogamine) and its demethylation product ibogamine [191, 195]. Hyperforin is a major antidepressant constituent of St. John s Wort (Hypericum perforatum) and inhibits serotonin uptake by elevating cytosolic Na+ [196]. The additional... 

Povlock, S. L. and Amara, S. G. The structure and function of noradrenaline, dopamine and 5-hydroxytryptamine transporters. In Neurotransmitter Transporters. Totowa, NJ Humana Press, 1999, pp. 1-28. 

Ramamoorthy, S., Cool, D.R., Leibach, F.H., Mahesh, V.B., Ganapathy, V. (1992). Reconstitution of the human placental 5-hydroxytryptamine transporter in a catalytically active form after detergent solubilization. Biochem. J. 286, 89-95. 

Kranzler HR, Armeli S, Tennen H, Covault J, Feinn R, Arias AJ, Pettinati H, Oncken C (2011) A double-blind, randomized trial of sertraline for alcohol dependence moderation by age of onset [corrected] and 5-hydroxytryptamine transporter-linked promoter region genotype. J Clin Psychopharmacol 31 22-30... 

Dizygotic twins 5-Hydroxytrypatmine 5-Hydroxytryptophan 5-Hydroytryptamine receptor 5-Hydroxytryptamine transporter... 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

This hypothesis, similarly, proposes that physical activity increases tryptophan transport into the presynaptic neurone, where it is used to synthesise 5-hydroxytryptamine. Hence, when the nerve is stimulated, more 5-hydroxytryptamine is released into the synapse and, if this is another inhibitory transmitter in the motor control pathway, it will inhibit contraction (Figure 13.28). This is one of several effects of 5-hydroxytryptamine in the brain which are probably achieved via different receptors on different neurones. All three hypotheses are summarised in Figure 13.29. 

Figure 30-28 Serotonin (5-hydroxytryptamine) and some drugs that affect receptors and transporters.

FIGURE 5—34. Serotonin (5-hydroxytryptamine [5HT ) is produced from enzymes after the amino acid precursor tryptophan is transported into the serotonin neuron. The tryptophan transport pump is distinct from the serotonin transporter (see Fig. 5—35). Once transported into the serotonin neuron, tryptophan is converted into 5-hydroxytryptophan (5HTP) by the enzyme tryptophan hydroxylase (TryOH) which is then converted into 5HT by the enzyme aromatic amino acid decarboxylase (AAADC). Serotonin is then stored in synaptic vesicles, where it stays until released by a neuronal impulse. 

Hajduch E, Rencurel F, Balendran A, Batty IH, Downes CP, Hundal HS. Serotonin (5-hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle. J Biol Chem 1999 274 13,563-13,568. 

Budhoo MR, Harris RP, Kellum JM. 5-Hydroxytryptamine-induced CL transport is mediated by 5-HT3 and 5-HT4 receptors in the rat distal colon. Eur J Pharmacol 1996 298 137-144. 

Raiteri M, Del Carmine R, Bertollini A, Levi G (1977) Effects of sympathomimetic amines on the synaptosomal transport of noradrenaline, dopamine and 5-hydroxytryptamine. Eur J Pharmacol 47 133-143. 

Serotonin or 5-hydroxytryptamine (5-HT), a monoamine, is widely distributed in many cells of the body and about 1-2% of the entire serotonin body content is found in the CNS. Serotonin is synthesized by the enzyme amino acid decarboxylase from 5-hydroxytryptophan (which is derived from tryptophan via tryptophan hydroxylase). The rate-limiting step is the production of 5-hydroxytryptophan by tryptophan hydroxylase. Serotonin is removed from the synapse by a high-affinity serotonin uptake site that is capable of transporting serotonin in either direction, depending on the concentration. 

Elangbam CS, Job LE, Zadrozny LM, et al. 5-hydroxytryptamine (5HT)-induced val-vulopathy Compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats. Exp Toxicol Pathol. 2008 60(4-5) 253-262. 

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). 

Li Q, Wichems C, Heils A, Van De Kar LD, Lesch KP, Murphy DL. 1999. Reduction of 5-hydroxytryptamine (5-HT)(lA)-mediated temperature and neuroendocrine responses and 5-HT(lA) binding sites in 5-HT transporter knockout mice. J. Pharmacol. Exp. Ther. 291 999-1007... 

Most antidepressants in clinical use today act by enhancing the neurotransmission of serotonin [5-hydroxytryptamine (5-HT)], norepinephrine [NE noradrenaline (NA)], or both. They do so either by blocking the reuptake (transport) of neurotransmitter, blocking the metabolism of neurotransmitter [i.e., monoamine oxidase (MAO) inhibitors], or by direct action on a neurotransmitter receptor. Hence, the antidepressants can be classified on the basis of their putative mechanisms of action (Table 8.2 and Figs. 8.1-8.4). Agents that block neurotransmitter reuptake can be further divided into those that are non-selective (e.g., tricyclic antidepressants with mixed action), serotonin-selective reuptake... 

Certain vitamins can be synthesized by humans in limited quantities. Niacin can be formed from tryptophan (Chapter 17). This pathway is not active enough to satisfy all the body s needs however, in calculating the RDA for niacin, 60 mg of dietary tryptophan is considered equivalent to 1 mg of dietary niacin. In Hartnup s disease (see Table 38-1 and Chapter 17), a rare hereditary disorder in the transport of monoaminomonocarboxylic acids (e.g., tryptophan), a pellagra-like rash may appear, suggesting that over a long period of time dietary intake of niacin is insufficient for metabolic needs. This pattern also occurs in carcinoid syndrome in which much tryptophan is shunted into the synthesis of 5-hydroxytryptamine. 

Pellagra-like symptoms can occur in Hartnup s disease and carcinoid syndrome. Hartnup s disease is an inherited disorder of amino acid transport (Chapter 17) in which niacin deficiency presumably develops because niacin intake is inadequate to supply metabolic needs when combined with the decreased absorption of dietary tryptophan. In carcinoid syndrome, up to 60% of available dietary tryptophan is diverted to formation of 5-hydroxytryptamine (serotonin) by what is normally a minor pathway. 

Serotonin, or 5-hydroxytryptamine (5-HT), is another monoamine whose important central effects have only been recognized recently. It had previously been known as a vasoconstrictor in the plasma. Once identified chemically, it was found to be widely distributed in the body. After determination of significant brain levels in the hypothalamus, medulla, midbrain, and other areas (Table 12-3), and after establishing its biosynthetic paths, serotonin became recognized as a neurotransmitter. 5-HT is presently less well understood than are the catecholamines. Figure 12-3 outlines its biosynthesis from the essential amino acid tryptophan. Try enters the brain by active transport (as is L-dopa) and is hydroxylated there by tryptophan hydroxylase, which is an enzyme similar to if not identical to, tyrosine hydroxylase. 

This mechanism acts in the inactivation of neiu-otransmitters as serotonin = 5-hydroxytryptamine (5-HT), noradrenaline = norepinephrine (NE) and dopamine (DA). The re-uptake is effected by selective transporters for each neurotransmitter. 

Serotonin (5-hydroxytryptamine, 5-HT) occurs in the intestinal wall, where it regulates motility and secretion in blood platelets, where it modulates platelet aggregation and vascular blood flow and in the CNS, where it acts as a neurotransmitter in areas of the midbrain. At least seven different receptors for serotonin have been characterized, which mediate a wide variety of different physiological effects. Depression and anxiety are thought to be the result of actions on 5-HTia receptors in the brain limbic system. Following release from neurons by a depolarizing action potential at central synapses, the activity of 5-HT is terminated by neuronal reuptake. This is performed by a synaptic membrane amine transporter protein, specific for 5-HT, which also co-transports sodium and chloride ions to repolarize the neuronal membrane. 

Serotonin, also known as 5-hydroxytryptamine (5-HT) is biosynthesized from tryptophan and is a neurotransmitter. Serotonin plays an important role in many behaviors including sleep, appetite, memory, and mood [52]. People with depressive disorders exhibit low levels of serotonin in the synapses. Protonated serotonin binds to a serotonin reuptake transporter protein, sometimes referred to as the serotonin transporter (SERT) and is then moved to an inward position on the neuron and subsequently released into the cjdoplasm. Selective serotonin reuptake inhibitors (SSRI) bind with high affinity to the serotonin binding site of the transporter. This leads to antidepressant effects by increasing extracellular serotonin levels which in turn enhances serotonin neurotransmission [53]. The SSRI class of antidepressants has fewer side effects than the monoamine oxidase inhibitors. 

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