A unique central tryptophan hydroxylase isoform

Walther, Diego J.; Bäder, Michael

doi:10.1016/s0006-2952(03)00556-2

Cited by 636 publications

(487 citation statements)

References 88 publications

Supporting

Mentioning

461

Contrasting

Unclassified

Order By: Relevance

“…The first step in 5-HT synthesis is the hydroxylation of tryptophan by tryptophan hydroxylase (Tph) forming 5-hydroxytryptophan (5-HTP). There are two isoforms of the enzyme; Tph1 which is predominantly expressed in the periphery, whereas Tph2 is predominantly expressed in the brain [38]. A Tph2 knockout in mice leads to retarded growth and lower body weight in early postnatal development [39,40].…”

Section: Brain 5-ht and Satietymentioning

confidence: 99%

“…The sites where exactly peripheral acting 5-HT agonists impact on satiety still require identification, although for 5-HT2 agonists the pylorus is a candidate [150]. Tph1 deficient mice show normal brain, but low peripheral 5-HT levels [38]. Tph1 knockout showed higher food intake, but unchanged locomotor activity, and gained more body weight.…”

Section: Peripheral 5-ht and Satietymentioning

confidence: 99%

See 1 more Smart Citation

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

View full text Add to dashboard Cite

Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

show abstract

Section: Brain 5-ht and Satietymentioning

confidence: 99%

Section: Peripheral 5-ht and Satietymentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

View full text Add to dashboard Cite

show abstract

“…Among them, we tested for alterations in the TPH1 and 2 genes, as well as the gene encoding the GTP-cyclohydrolase I feedback regulatory protein (GFRP, GCHFR gene). Whereas both tetrahydrobiopterindependent TPH isoforms are rate limiting enzymes for serotonin biosynthesis [22,23], the GFRP was reported to be expressed in specific brain tissues and potentially be involved in the regulation of tetrahydrobiopterin biosynthesis in serotonin (but not dopamine) neurons [24]. Only wild-type sequences were found for the TPH1/2 and GCHFR genes (not shown).…”

Section: Resultsmentioning

confidence: 99%

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants

Adamsen

Meili

Blau

et al. 2011

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid-compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4½ years. Low levels of the serotonin endmetabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant. These changes are reported to be responsible for elevated SERT activity and expression, suggesting that these alterations were responsible in our patient for low serotonin turnover in the central nervous system (CNS). Daily treatment with 5-hydroxytryptophan (and carbidopa) led to clinical improvement and normalization of 5HIAA, implying that brain serotonin turnover normalized. We speculate that the mutated 56Ala SERT transporter with elevated expression and basal activity for serotonin re-uptake is accompanied with serotonin accumulation within pre-synaptic axons and their vesicles in the CNS, resulting in a steady-state of lowered serotonin turnover and degradation by monoamine-oxidase (MAO) enzymes in pre-synaptic or neighboring cells.

show abstract

“…Approximately 95% of total serotonin in the human body is released within the gastrointestinal tract: approximately 10% by the enteric neurons and 90% by the enterochromaffin cells. The remaining 5% exerts its action in the brain, crossing the blood-brain barrier [18].…”

Section: Serotonin Synthesis and Physiologymentioning

confidence: 99%

“…This enzyme is essential because it is considered the rate-limiting step of the systemic and neuronal synthesis of serotonin. TPH has two isoforms: TPH2 (located only in the brain) and TPH1 (located in the peripheral tissues with no presence in the CNS and encoded by a different gene) [18,19]. L-Amino acid decarboxylase is the catalyzed enzyme involved in the second step of serotonin synthesis [20,21] (Fig.…”

Section: Serotonin Synthesis and Physiologymentioning

confidence: 99%

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

et al. 2016

View full text Add to dashboard Cite

The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being reduced by approximately 50% within the first year. The exact mechanisms of resistance to SSAs are not fully understood, but it is believed that serotonin might be involved. Patients with carcinoid syndrome present with a significant increase in serotonin plasma levels and, consequently, in the soluble urinary metabolite 5‐hydroxyindole acetic acid. Telotristat etiprate is a potent inhibitor of tryptophan hydroxylase, a rate‐limiting enzyme in the synthesis of serotonin, that has demonstrated in the phase III TELESTAR clinical trial a significant improvement in the control of bowel movements in patients with NETs who have carcinoid syndrome and who have progressed to an SSA. Based on these results, telotristat etiprate has emerged as a potential new option in the treatment algorithm of symptomatic control of functioning NETs. However, some issues need to be clarified, such as the safety profile of the drug outside clinical trials, the benefit in quality of life, and the possible impact on tumor growth, as well as its role within sequencing or combination treatment strategies with pre‐existing drugs effective in NET treatment. Implications for Practice: This article reviews the literature about carcinoid syndrome, which affects patients diagnosed with neuroendocrine tumors. Few articles have been published about this syndrome and its pathophysiology. Somatostatin analogs provide symptomatic relief; however, patients may become refractory to this strategy, usually within the first year of treatment. In this context, as an agent with an innovative mechanism of action, telotristat etiprate has demonstrated activity in a phase III trial, and findings may offer a path to an improve quality of life and prolonged survival for certain patients.

show abstract

A unique central tryptophan hydroxylase isoform

Cited by 636 publications

References 88 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

Contact Info

Product

Resources

About