Contribution of Serotonin 3A Receptor to Motor Function and Its Expression in the Gastrointestinal Tract

Aikiyo, Satoshi; Kishi, Kazuhisa; Kaji, Noriyuki; Mikawa, Shoma; Kondo, Makoto; Shimada, Shoichi; Hori, Masaru

doi:10.1159/000509209

Cited by 6 publications

(5 citation statements)

References 33 publications

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“…These data are the first to suggest that 5-HT2A receptor activation in neuroblastoma cells causes significant downregulation in the 5ht3A gene -which encodes a ligand-gated ionic channel important in mediating fast depolarizing responses underlying dopamine release in the striatum [20]. The 5ht3a gene is also expressed in the gut and has a role in intestinal motility [26]. Dysregulating gastrointestinal motility is a common complication in patients suffering with Parkinson's disease.…”

Section: Discussionmentioning

confidence: 77%

Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes

2021

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Traumatic brain injury and adult type 2 diabetes mellitus are each associated with the late occurrence of accelerated cognitive decline and Parkinson’s disease through unknown mechanisms. Previously, we reported increased circulating agonist autoantibodies targeting the 5-hydroxytryptamine 2A receptor in plasma from subsets of Parkinson’s disease, dementia, and diabetic patients suffering with microvascular complications. Here, we use a model neuron, mouse neuroblastoma (N2A) cell line, to test messenger RNA expression changes following brief exposure to traumatic brain injury and/or type 2 diabetes mellitus plasma harboring agonist 5-hydroxytryptamine 2A receptor autoantibodies. We now report involvement of the mitochondrial dysfunction pathway and Parkinson’s disease pathways in autoantibody-induced gene expression changes occurring in neuroblastoma cells. Functional gene categories upregulated significantly included cell death, cytoskeleton-microtubule function, actin polymerization or depolymerization, regulation of cell oxidative stress, mitochondrial function, immune function, protein metabolism, and vesicle function. Gene categories significantly downregulated included microtubule function, cell adhesion, neurotransmitter release, dopamine metabolism synaptic plasticity, maintenance of neuronal differentiation, mitochondrial function, and cell signaling. Taken together, these results suggest that agonist 5-hydroxytryptamine receptor autoantibodies (which increase in Parkinson’s disease and other forms of neurodegeneration) mediate a coordinating program of gene expression changes in a model neuron which predispose to neuro-apoptosis and are linked to human neurodegenerative diseases pathways.

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Section: Discussionmentioning

confidence: 77%

Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes

2021

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“…Serotonin (5-HT) plays an important role in the regulation of sleep, mood, and digestion as a neurotransmitter and a peripheral hormone [40][41][42][43]. In serotonergic neurons, 5-HT-containing vesicles are released by exocytosis via the SNARE complex containing v-SNARE (synaptobrevins/VAMPs) and t-SNARE (syntaxins and synaptosomal-associated proteins), and binding of released 5-HT to its autoreceptor (such as 5-HT1A) induces negative feedback to suppress further release of 5-HT [44,45].…”

Section: Discussionmentioning

confidence: 99%

Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

Kondo,

Suzuki,

Matsumura

et al. 2023

Eur J Immunol

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In the present study, we found that methiothepin (a non‐selective 5‐hydroxytryptamine (5‐HT) receptor antagonist) inhibited antigen‐induced degranulation in rat basophilic leukemia cells and mouse bone marrow‐derived mast cells. Although antigen stimulation induces release of histamine and serotonin (5‐HT) by exocytosis and mast cells express several types of 5‐HT receptor, the detailed role of these receptors remains unclear. Here, pretreatment of cells with methiothepin attenuated increased intracellular Ca2+ concentration, phosphorylated critical upstream signaling components: SFKs, Syk, and PLCγ1, and suppressed TNF‐α secretion via inhibition of Akt and ERK phosphorylation. Furthermore, it inhibited PMA/ionomycin‐induced degranulation; this finding suggested that methiothepin affected downstream signaling. IκB kinase β (IKKβ) phosphorylates synaptosomal associated protein 23 (SNAP23), which regulates the fusion events of the secretory granule/plasma membrane after mast cell activation, resulting in degranulation. We showed that methiothepin blocked PMA/ionomycin‐induced phosphorylation of SNAP23 by inhibiting its interaction with IKKβ. Together with the results of selective 5‐HT antagonists, it is suggested that methiothepin inhibits mast cell degranulation by downregulating upstream signaling pathways and exocytotic fusion machinery through mainly 5‐HT1A receptor. Our findings provide that 5‐HT antagonists may be used to relieve allergic reactions.This article is protected by copyright. All rights reserved

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“…These receptors are expressed in cholinergic nerves and PDGFRα-positive cells in the myenteric plexus, directly influencing motility. Their activation accelerates gastric emptying and colon transit [ 76 ]. 5-HT3 receptors play a role in rotavirus –induced diarrhea.…”

Section: Serotonin In the Gi Tractmentioning

confidence: 99%

“…The cardiac risk is thought to be related to its affinity for hERG channels, which results in QT prolongation and is enhanced by the concomitant use of inhibitors of CYP involved in cisapride metabolism [ 95 ]. Nevertheless, cisapride was withdrawn from the US market in 2000 [ 76 ] and suspended from the European market in 2002 [ 96 ] due to serious adverse cardiac events. The affinity of the 5-HT4 receptor for particular ligands has been noted to depend on which COOH-terminal splice variant is expressed by a particular cell.…”

Section: Serotonin In the Gi Tractmentioning

confidence: 99%

The Role of Serotonin Neurotransmission in Gastrointestinal Tract and Pharmacotherapy

Guzel

Mirowska‐Guzel

2022

Molecules

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5-Hydroxytryptamine (5-HT, serotonin) is a neurotransmitter in both the central nervous system and peripheral structures, acting also as a hormone in platelets. Although its concentration in the gut covers >90% of all organism resources, serotonin is mainly known as a neurotransmitter that takes part in the pathology of mental diseases. Serotonin modulates not only CNS neurons, but also pain transmission and platelet aggregation. In the periphery, 5-HT influences muscle motility in the gut, bronchi, uterus, and vessels directly and through neurons. Serotonin synthesis starts from hydroxylation of orally delivered tryptophan, followed by decarboxylation. Serotonin acts via numerous types of receptors and clinically plays a role in several neural, mental, and other chronic disorders, such as migraine, carcinoid syndrome, and some dysfunctions of the alimentary system. 5-HT acts as a paracrine hormone and growth factor. 5-HT receptors in both the brain and gut are targets for drugs modifying serotonin neurotransmission. The aim of the present article is to review the 5-HT receptors in the gastrointestinal (GI) tract to determine the role of serotonin in GI physiology and pathology, including known GI diseases and the role of serotonin in GI pharmacotherapy.

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Contribution of Serotonin 3A Receptor to Motor Function and Its Expression in the Gastrointestinal Tract

Cited by 6 publications

References 33 publications

Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes

Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes

Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

The Role of Serotonin Neurotransmission in Gastrointestinal Tract and Pharmacotherapy

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