Serotonin receptors and valvular heart disease
Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner in Endocrine Surgery, 2017
5-Hydroxytryptamine (5-HT) or serotonin is a vital cellular signaling molecule mostly present in the central and peripheral nervous systems (serotoninergic neurons), gastrointestinal tract (intestinal myenteric plexus and enterochromaffin cells), bronchopulmonary system (enterochromaffin cells) and cardiovascular system (blood platelets) [1]. While serotoninergic neurons and enterochromaffin cells can synthesize serotonin, platelets only rely on uptake mechanisms to proceed with serotonin storage [2]. The synthesis of serotonin is a complex biochemical pathway that initially involves the conversion of the essential amino acid L-tryptophan to 5-hydroxytryptophan (5-HTP) by the enzyme L-tryptophan hydroxylase (TPH) [3]. It is important to highlight that this reaction is a rate-limiting step for serotonin production in non-neuronal tissues. Subsequently, the aromatic L-amino acid decarboxylase (AADC) catalyzes the final production of 5-HT, and this is internalized by the vesicular monoamine transporter (VMAT) and released to induce both autocrine and paracrine actions [4] (Figure 46.1a).
Studies on the Neurobiology of Depression
Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen in Handbook of Depression and Anxiety, 2003
Serotonin is synthesized from the amino acid tryptophan, which is derived from the diet. The rating-limiting step in serotonin synthesis is the hydroxylation of tryptophan by the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan. Under normal circumstances, this rating-limiting enzyme is not saturated by substrate, so tryptophan concentration can impact the rate of synthesis. Tryptophan is then taken up into brain via a saturable carrier mechanism. Tryptophan actively competes with other large neutral amino acids for transport; brain uptake of tryptophan is determined both by the amount of circulating tryptophan and by the ratio of tryptophan to the other large neutral amino acids. This ratio may be affected (elevated) by carbohydrate intake, which induces the release of insulin and the uptake of many large neutral amino acids into peripheral tissues. High-protein foods tend to be relatively low in tryptophan, thus lowering this ratio. The administration of specialized low-tryptophan diets has been found to produce significant declines in the brain serotonin levels.
Neurotransmitters and pharmacology
Mark J. Ashley, David A. Hovda in Traumatic Brain Injury, 2017
The rate-limiting step in the overall conversion of tryptophan to serotonin is the first step that is catalyzed by TPH (Figure 16.9) and results in the conversion of tryptophan to 5-hydroxytryptophan (5-HTP). Like tyrosine hydroxylase, tryptophan hydroxylase is a cytoplasmic mixed-function oxidase that requires molecular oxygen and a reduced pteridine as cofactors. It should also be noted that a membrane-associated form of tryptophan hydroxylase has been found, indicating that some of the enzyme may be membrane bound. Two isoforms of tryptophan hydroxylase (tryptophan hydroxylase-1 and tryptophan hydroxylase-2) have been identified. Tryptophan hydroxylase-2 (TPH2) is the one that is expressed primarily in the brain.107 Polymorphisms (alterations) in the gene that codes for TPH2 may be associated with altered susceptibility to affective disorders (e.g., depression) and one’s responsiveness to antidepressants.1 Various inhibitors of tryptophan hydroxylase have been identified, the best known of which is parachlorophenylalanine (PCPA), which has been used experimentally to study the function of 5-HT.
LIM kinase inhibitor T56-LIMKi protects mouse brain from photothrombotic stroke
Published in Brain Injury, 2021
Svetlana V. Demyanenko, Anatoly Uzdensky
Protein kinase DYRK1A regulates proliferation, differentiation and apoptosis in the developing brain (47). In the adult brain, its overexpression leads to disruption of various signaling pathways, loss of neurons, aging and development of various neurodegenerative diseases (22). Under oxidative stress, DYRK1A stimulates neuronal apoptosis (48). Its inhibitor harmine was shown to reduce cerebral edema, inflammation, and apoptosis of neurons caused by ischemic or traumatic brain injury (49,50). However, in the present experiments harmine was ineffective. Tryptophan hydroxylase mediates serotonin biosynthesis in serotoninergic neurons. Its inhibition by PCPA also did not protect the mouse brain from the PTS consequences. Possibly, these neurochemical processes were not involved in the protection of the peri-infarct region cells after PTS.
Impaired serotonin communication during juvenile development in rats diminishes adult sperm quality
Published in Systems Biology in Reproductive Medicine, 2018
Juan Díaz-Ramos, Maribel Flores-Flores, María E. Ayala, Andrés Aragón-Martínez
Serotonin is a neurotransmitter produced by neurons in the central nervous system and is also present in organs such as the testis (Campos et al. 1990; Tinajero et al. 1993; Frungieri et al. 1999; Gerendai et al. 2007). Serotonin, serotonin receptors, and enzymes involved in serotonin biosynthesis and metabolism, are present in distinct locations of the testis. Serotonin is present in the capsule, mastocytes, platelets, and Leydig cells (Aguilar et al. 1995; Campos et al. 1990; Tinajero et al. 1993; Frungieri et al. 1999); testicular serotonin also arises from the spermatic nerve (Campos et al. 1990; Frungieri et al. 1999). Serotonin receptors 5-HT1 and 5-HT2 are present in Leydig cells (Tinajero et al. 1992; Frungieri et al. 2002). The enzyme tryptophan hydroxylase (TPH) is the limiting factor in the serotonin biosynthetic pathway and is located in the Leydig cells (Tinajero et al. 1992). Monoamine oxidase (MAO) metabolizes serotonin and is present in the wall of seminiferous tubules (Ellis et al. 1972).
Emerging therapies in the management of Irritable Bowel Syndrome (IBS)
Published in Expert Opinion on Emerging Drugs, 2022
Jill E. Elwing, Hadi Atassi, Benjamin D. Rogers, Gregory S. Sayuk
For several decades now, the serotonergic system has been a key target in the development of novel IBS therapies. More than 90% of the serotonin (5-HT) present in humans can be localized to the GI tract, the vast majority contained within the epithelial enterochromaffin cells, and a small percentage within the enteric nervous system. 5-HT is known to have an important role in GI motility, secretion, and visceral sensitivity, and accordingly is regarded to be a key neurotransmitter in IBS pathophysiology [64]. Seven distinct subtypes of 5-HT receptors have been identified in the brain and gut, with 5-HT3 receptors localized to the intestinal nerve plexuses, including sympathetic and parasympathetic nerves [65]. As previously noted, the 5-HT3 antagonist alosetron is FDA-approved for the treatment of IBS with diarrhea. Further, 5-HT4 agonists have been developed for constipation-predominant patients and tegaserod has been developed and approved for the management of IBS-D. Tryptophan hydroxylase is responsible for the initial -OH addition (hydroxylation) to the 5 position to form the amino acid 5-hydroxytryptophan (5-HTP), the rate-limiting step in the synthesis of serotonin. Orally bioavailable, small-molecule tryptophan 5–hydroxylase (TPH) inhibitors, resulting in reductions in serotonin synthesis in the intestine, are being explored for IBS treatment [66].
Related Knowledge Centers
- Cofactor
- Dihydrobiopterin
- Enzyme
- Tetrahydrobiopterin
- Tryptophan
- Tyrosine Hydroxylase
- Serotonin
- Phenylalanine Hydroxylase
- Biopterin-Dependent Aromatic Amino Acid Hydroxylase
- 5-Hydroxytryptophan