Switching-on of serotonergic calcium signaling in activated hepatic stellate cells

Park, Kyu Sang; Sin, Pyo Jin; Lee, Dong Hyeon; Kuy, Seung; Kim, Min Jeong; Kim, Na Hyun; Baik, Soon Koo; Jeong, Seong Woo; Kong, In Deok

doi:10.3748/wjg.v17.i2.164

Cited by 14 publications

(12 citation statements)

References 38 publications

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“…Of particular relevance to portal hypertension, platelet-derived serotonin in a model of viral hepatitis results in hepatic microcirculatory dysfunction in the sinusoids leading to reduced flow [95], consistent with other studies demonstrating serotonin-mediated low sinusoidal flow reversed by serotonin receptor antagonism [96,97]. This effect may be mediated by serotonin-induced calcium influx into sinusoidal endothelial cells and myosin light chain phosphorylation causing fenestral contraction [98,99], or by serotonin-mediated HSC activation, possibly through increasing intracellular calcium [100,101].…”

Section: Plateletssupporting

confidence: 70%

“…Thrombin may activate HSCs through protease-activated receptor 1 (PAR1) [134] as well as promote platelet aggregation/activation through PAR4 [135], with platelet adhesion to the endothelium mediated by glycoprotein (GP) Ib and the integrins aIIb3 and aVb3 [136]. Platelets can then activate HSCs through release of serotonin [100,101] and platelet-derived growth factor B (PDGF-B) [137]. Serotonin also leads to increased myosin light chain phosphorylation (P-MLC) in LSECs, fenestral contraction, and microvascular dysfunction [98,99].…”

Section: Immune Cellsmentioning

confidence: 99%

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Biology of portal hypertension

McConnell

Iwakiri

2017

Hepatol Int

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Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.

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Section: Plateletssupporting

confidence: 70%

Section: Immune Cellsmentioning

confidence: 99%

Biology of portal hypertension

McConnell

Iwakiri

2017

Hepatol Int

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“…For example, [Ca 2+ ]i mobilization is implicated in the differentiation (activation) of hepatic stellate cells (HSCs) and portal (myo)fibroblasts during liver fibrosis (198, 292). HSC and portal fibroblasts express receptors for several Ca 2+ -mobilizing agonists, such as endothelin (198, 322), platelet-derived growth factor (PDGF) (86, 110), vasopressin (305) and ATP (102, 316), and upregulation of serotonin (5-HT2) receptors may be observed after HSC activation (292). Liver myofibroblast activation may exhibit different profiles of Ca 2+ responses to endothelin and PDGF (198).…”

Section: General Molecular and Cellular Mechanisms Of Ca2+ Signalingmentioning

confidence: 99%

Calcium Signaling in the Liver

Amaya

Nathanson

2013

Comprehensive Physiology

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Intracellular free Ca2+ ([Ca2+]i) is a highly versatile second messenger that regulates a wide range of functions in every type of cell and tissue. To achieve this versatility, the Ca2+ signaling system operates in a variety of ways to regulate cellular processes that function over a wide dynamic range. This is particularly well exemplified for Ca2+ signals in the liver, which modulate diverse and specialized functions such as bile secretion, glucose metabolism, cell proliferation, and apoptosis. These Ca2+ signals are organized to control distinct cellular processes through tight spatial and temporal coordination of [Ca2+]i signals, both within and between cells. This article will review the machinery responsible for the formation of Ca2+ signals in the liver, the types of subcellular, cellular, and intercellular signals that occur, the physiological role of Ca2+ signaling in the liver, and the role of Ca2+ signaling in liver disease.

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“…However, research on liver fibrogenesis has delineated the presence of several of these receptors on hepatic stellate cells (HSCs). It is known that HSCs can build calcium currents and thus get activated by 5-HT via the 5HT2 receptor (Park et al, 2011 ). Furthermore, rat and human HSCs possess the 5-HT1B, 5-HT1F 5-HT2A 5-HT2B, and 5-HT7 receptors, where 5-HT2B was shown to closely correlate to the degree of fibrosis in experimental liver fibrosis induced by carbon tetrachloride (Ruddell et al, 2006 ).…”

Section: The “Third Party” In Nerve-cancer Interactions: Desmoplasia mentioning

confidence: 99%

Nerve-cancer interactions in the stromal biology of pancreatic cancer

2012

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Interaction of cancer cells with diverse cell types in the tumor stroma is today recognized to have a fate-determining role for the progression and outcome of human cancers. Despite the well-described interactions of cancer cells with several stromal components, i.e., inflammatory cells, cancer-associated fibroblasts, endothelial cells, and pericytes, the investigation of their peculiar relationship with neural cells is still at its first footsteps. Pancreatic cancer (PCa) with its abundant stroma represents one of the best-studied examples of a malignant tumor with a mutually trophic interaction between cancer cells and the intratumoral nerves embedded in the desmoplastic stroma. Nerves in PCa are a rich source of neurotrophic factors like nerve growth factor (NGF), glial-cell-derived neurotrophic factor (GDNF), artemin; of neuronal chemokines like fractalkine; and of autonomic neurotransmitters like norepinephrine which can all enhance the invasiveness of PCa cells via matrix-metalloproteinase (MMP) upregulation, trigger neural invasion (NI), and activate pro-survival signaling pathways. Similarly, PCa cells themselves provide intrapancreatic nerves with abundant trophic agents which entail a remarkable neuroplasticity, leading to emergence of more routes for NI and cancer spread, to augmented local neuro-surveillance, neural sensitization, and neuropathic pain. The strong correlation of NI with PCa-associated desmoplasia suggests the potential presence of a triangular relationship between nerves, PCa cells, and other stromal partners like myofibroblasts and pancreatic stellate cells which generate tumor desmoplasia. Hence, although not a classical hallmark of human cancers, nerve-cancer interactions can be considered as an indispensable sub-class of cancer-stroma interactions in PCa. The present article provides an overview of the so far known nerve-cancer interactions in PCa and illustrates their ominous role in the stromal biology of human PCa.

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Switching-on of serotonergic calcium signaling in activated hepatic stellate cells

Abstract: The appearance of 5-HT-induced [Ca²+](i) response accompanied by upregulation of metabotropic 5-HT₂ receptors and Ca²+ transporting/chaperone ER proteins may participate in the activating process of HSCs.

Cited by 14 publications

References 38 publications

Biology of portal hypertension

Biology of portal hypertension

Calcium Signaling in the Liver

Nerve-cancer interactions in the stromal biology of pancreatic cancer

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