Mechanical stimulation activates Gαq signaling pathways and 5-hydroxytryptamine release from human carcinoid BON cells

Kim, Min‐Soo; Javed, Najma; Yu, Jun-Ge; Christofi, Fievos L.; Cooke, Helen J.

doi:10.1172/jci12467

Cited by 75 publications

(55 citation statements)

References 45 publications

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“…Since that time, it has been demonstrated in a number of experimental paradigms, including human preparations, that stroking of the mucosal surface results in 5-HT release 19, 74–76 . Serotonin release can also be induced by mechanical stimulation of BON cells, a human cell line model of EC cells 77 . It is clear from the elegant studies of groups led by Jack Grider 78 , Terry Smith 79 , and Joel Bornstein 31, 80 that 5-HT released in response to mucosal stimulation can activate the ascending contractile and descending relaxant limbs of the peristaltic reflex.…”

Section: Functions Of 5-ht In the Gastrointestinal Tractmentioning

confidence: 99%

“…The afferent neurons receive signals from projections to the lamina propria, and when stimulated, they synaptically activate secretomotor neurons, which in turn, release neurotransmitters such as acetylcholine and vasoactive intestinal peptide (VIP) to activate secretion from the epithelial cells. Serotonin released from EC cells is an important activator of these reflex-mediated secretory responses 77, 91, 92 . Mechanical stimulation of the mucosal surface leads to 5-HT release, which activates neurally mediated Cl - and bicarbonate secretion.…”

Section: Functions Of 5-ht In the Gastrointestinal Tractmentioning

confidence: 99%

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Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

884

783

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Serotonin (5-HT) has been recognized for decades as an important signaling molecule in the gut, but it is still revealing its secrets. We continue to discover novel gastrointestinal (GI) functions of 5-HT, as well as actions of gut-derived 5-HT outside of the gut, and we are learning how 5-HT signaling is altered in GI disorders. Furthermore, new therapeutic targets related to 5-HT signaling are being identified that can hopefully be exploited to alleviate the symptoms of functional GI disorders. Conventional functions of 5-HT in the gut involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion, and vasodilation. Activation of extrinsic vagal and spinal afferent fibers results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts non-conventional actions that include serving as a pro-inflammatory signaling molecule and as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, which comes from the gut, can promote hemostasis, influence bone development, and contribute to allergic airway inflammation. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhea or constipation, respectively. More recently, the synthetic enzyme, tryptophan hydroxylase has been targeted, and there are recent findings suggesting that epithelial 5-HT4 receptors could be targeted to provide a safe and effective treatment for constipation. Here we provide an overview of these serotonergic actions and treatment strategies.

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Section: Functions Of 5-ht In the Gastrointestinal Tractmentioning

confidence: 99%

Section: Functions Of 5-ht In the Gastrointestinal Tractmentioning

confidence: 99%

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

884

783

View full text Add to dashboard Cite

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“…Zhang and coauthors (38) have shown that phorbol ester treatment of BON cells results in a persistent release and cellular depletion of chromogranin A through a PKC-dependent pathway. Furthermore, Kim and colleagues (18) have shown that mechanical stimulation of BON cells led to increased levels of 5-HT secretion. They determined the mechanism of this enhanced hormone release was stimulation of a G protein-coupled receptor leading to mobilization of intracellular calcium (18).…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, Kim and colleagues (18) have shown that mechanical stimulation of BON cells led to increased levels of 5-HT secretion. They determined the mechanism of this enhanced hormone release was stimulation of a G protein-coupled receptor leading to mobilization of intracellular calcium (18). Recently, 5-HT secretion by BON cells has been studied by acetylcholine and calcium stimulation (34).…”

Section: Discussionmentioning

confidence: 98%

Conservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells

Kunnimalaiyaan¹,

Traeger²,

Chen³

2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Gastrointestinal (GI) carcinoid cells secrete multiple neuroendocrine (NE) markers and hormones including 5-hydroxytryptamine and chromogranin A. We were interested in determining whether activation of the Notch1 signal transduction pathway in carcinoid cells could modulate production of NE markers and hormones. Human pancreatic carcinoid cells (BON cells) were stably transduced with an estrogen-inducible Notch1 construct, creating BON-NIER cells. In the present study, we found that Notch1 is not detectable in human GI carcinoid tumor cells. The induction of Notch1 in human BON carcinoid cells led to high levels of functional Notch1, as measured by CBF-1 binding studies, resulting in activation of the Notch1 pathway. Similar to its developmental role in the GI tract, Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein and a concomitant silencing of human Notch1/HES-1/achaete-scute homolog 1. Furthermore, Notch1 activation led to a significant reduction in NE markers. Most interestingly, activation of the Notch1 pathway caused a significant reduction in 5-hydroxytryptamine, an important bioactive hormone in carcinoid syndrome. In addition, persistent activation of the Notch1 pathway in BON cells led to a notable reduction in cellular proliferation. These results demonstrate that the Notch1 pathway, which plays a critical role in the differentiation of enteroendocrine cells, is highly conserved in the gut. Therefore, manipulation of the Notch1 signaling pathway may be useful for expanding the targets for therapeutic and palliative treatment of patients with carcinoid tumors.

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“…2 The human carcinoid BON cells is an established hEC line shown to be a suitable model to study both chemo- and mechanosensation, in addition to receptor regulation, postreceptor signaling pathways, and physiological regulation of 5-HT release. 1,2,18–21 We found that a major component of mechanosensation is activation of the Gα q /phospholipase C (PLC)/Ca 2+ signaling pathway to increase 5-HT release. Because 5-HT release is a Ca 2+ -dependent pathway, study of intracellular free Ca 2+ levels in BON cells is a suitable target to study regulation of 5-HT release mechanisms at a single cell level.…”

mentioning

confidence: 99%

Purinergic Autocrine Regulation of Mechanosensitivity and Serotonin Release in a Human EC Model

Liñán-Rico

Wunderlich

Grants

et al. 2013

Inflammatory Bowel Diseases

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Background Alterations in 5-hydroxytryptamine (HT) signaling in inflamed gut may contribute to pathogenesis of inflammatory bowel diseases. Adenosine 5′-triphosphate (ATP) regulates mucosal-mechanosensory reflexes and ATP receptors are sensitive to mucosal inflammation. Yet, it remains unknown whether ATP can modulate 5-HT signaling in enterochromaffin cells (EC). We tested the novel purinergic hypothesis that ATP is a critical autocrine regulator of EC mechanosensitivity and whether EC expression of ATP-gated P2X3-ion channels is altered in inflammatory bowel diseases. Methods Laser confocal (fluo-4) Ca2+ imaging was performed in 1947 BON cells. Chemical stimulation or mechanical stimulation (MS) was used to study 5-HT or ATP release in human BON or surgical mucosal specimens, and purine receptors by reverse transcription-polymerase chain reaction, Western Blot, or P2X3-immunoreactivity in BON or 5-HT+ human EC (hEC) in 11 control and 10 severely inflamed ulcerative colitis (UC) cases. Results ATP or MS triggered Ca2+-transients or 5-HT release in BON. ATP or adenosine diphosphate increased 5-HT release 5-fold. MS caused ATP release, detected after 5′ecto-ATPase inhibition by ARL67156. ARL67156 augmented and apyrase blocked Ca2+/5-HT mechanosensitive responses. 2-Methyl-thio-adenosine diphosphate 5′-monophosphate-evoked (P2Y1,12) or mechanically-evoked responses were blocked or augmented by a P2Y1,12 antagonist, MRS2179, in different cells or inhibited by U73122. A P2Y12 antagonist, 2MeSAMP, augmented responses. A P2X1,3 agonist, α,β-MeATP, triggered Ca2+ responses, whereas a P2X1,2/3,3 antagonist, 2′,3′-O-(2,4,6-trinitrophenyl)-ATP, blocked mechanical responses or cell-surface 5′ATP-TR labeling. In hEC, α,β-MeATP stimulated 5-HT release. In UC, P2X3-immunoreactivity decreased from 15% to 0.2% of 5-HT+hECs. Human mucosa and BON expressed P2X1, P2X3, P2X4, P2X5, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, and P2Y12R-messenger RNA transcripts. Conclusions ATP is a critical determinant of mechanosensation and 5-HT release via autocrine activation of slow P2Y1-phospholipase C/inositol-1,4,5-triphosphate-Ca2+ or inhibitory P2Y12-purinergic pathways, and fast ATP-gated P2X3-channels. UC downregulation of P2X3-channels (or A2B) is postulated to mediate abnormal 5-HT signaling.

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Mechanical stimulation activates Gαq signaling pathways and 5-hydroxytryptamine release from human carcinoid BON cells

Cited by 75 publications

References 45 publications

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Conservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells

Purinergic Autocrine Regulation of Mechanosensitivity and Serotonin Release in a Human EC Model

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