Sphingosine 1-phosphate receptor 2/adenylyl cyclase/protein kinase A pathway is involved in taurolithocholate-induced internalization of Abcc2 in rats

Andermatten, Romina Belén; Ciriaci, Nadia; Schuck, V.; Siervi, Nicolás Di; Razori, María Valeria; Miszczuk, Gisel Sabrina; Medeot, Anabela Carolina; Davio, Carlos; Crocenzi, Fernando A.; Roma, Marcelo G.; Barosso, Ismael Ricardo; Pozzi, Enrique J. Sánchez

doi:10.1007/s00204-019-02514-6

Cited by 6 publications

(3 citation statements)

References 53 publications

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“…These results suggest there are conformational changes in S1PR2 after BA addition likely associated with induced signaling pathways. These would be consistent with structural and functional properties of S1PR2 activation in other systems (24, 25). Finally, replication of two other BA-requiring strains, GII.17 and GI.1, was inhibited by S1PR2 inhibition, suggesting that a common entry and infection pathway is used by these strains independent of the genogroup (GI versus GII).…”

Section: Discussionsupporting

confidence: 87%

Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition

Tenge,

Vijayalakshmi Ayyar,

Ettayebi

et al. 2024

Preprint

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Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause both endemic and pandemic acute viral gastroenteritis. Previously we reported that many strains of HuNoV require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. Of note, BA was not essential for replication of a pandemic-causing GII.4 HuNoV strain. Using the BA-requiring strain GII.3, we found that the hydrophobic BA GCDCA induces multiple cellular responses that promote replication in jejunal enteroids. Further, we found that chemical inhibition of the G-protein coupled receptor, sphingosine-1- phosphate receptor 2 (S1PR2), by JTE-013 reduced both GII.3 infection in a dose- dependent manner and cellular uptake in enteroids. Herein, we sought to determine if S1PR2 is required by other BA-dependent HuNoV strains and BA-independent GII.4, and if S1PR2 is required for BA-dependent HuNoV infection in other segments of the small intestine. We found JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not the GII.4 Sydney variant (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. GII.3 infection of duodenal, jejunal and ileal lines derived from the same individual was also reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoV exploit the activation of S1PR2 by BA to infect the entire small intestine.ImportanceHuman noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA- independent strain, all required S1PR2 for infection. Additionally, BA-dependent infection required S1PR2 in multiple segments of the small intestine. Together these results indicate S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.

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Section: Discussionsupporting

confidence: 87%

Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition

Tenge,

Vijayalakshmi Ayyar,

Ettayebi

et al. 2024

Preprint

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“…PKs contain serine (Ser), threonine (Thr) and tyrosine (Tyr) residues, or lysine (Lys), histidine (His) and arginine (Arg) residues. Various PKs, such as PKB (Akt) and PKC, regulate the localization of hepatic bile transporters after transcription, and the activation of phosphoinositide-3-kinase (PI3K)/Akt signaling causes sustained internalization of MRP2 and BSEP, thus eventually leading to cholestasis [79,80]. Via second messengers, PKs initiate signaling cascades, regulate the phosphorylation and dephosphorylation of the hepatobiliary transport system and corresponding crosslinked proteins or scaffolding proteins, alter the membrane localization of transporters and rapidly adjust bile composition, thus subsequently promoting cholestasis and/or exerting choleretic effects.…”

Section: Localization Regulation Of Hepatic Transportersmentioning

confidence: 99%

Molecular mechanisms of transporter regulation and their impairment in intrahepatic cholestasis

et al. 2022

Acta Materia Medica

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Intrahepatic cholestasis (IC) is a liver disease caused by disorders in bile formation and excretion, owing to structural and functional abnormalities in hepatocytes and/or bile capillaries. IC is commonly caused by hepatitis virus, alcohol consumption, drug-induced liver damage, autoimmune liver disease and heredity. In the absence of effective treatment, IC can progress to liver fibrosis, cirrhosis and ultimately liver failure. However, the mechanisms underlying IC remain poorly understood. IC is believed to be closely associated with changes in the transcription, function and localization of hepatocellular transport proteins. To better understand the molecular mechanisms of transport proteins in IC, herein, we review the roles of these transport proteins and discuss their underlying regulatory mechanisms in IC. Our aim is to provide a reference for understanding IC pathogenesis and developing effective drug therapies.

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“…Previous works demonstrated that E 2 17G reduces the expressions of transporters on the membrane through the activation of different signaling proteins to cause their insertion ( Mottino et al, 2002 ; Mottino et al, 2005 ; Crocenzi et al, 2008 ). Up to now, there are lots of evidence demonstrated that the protein kinase C (PKC), ERα, p38-MAPK, epidermal growth factor receptor (EGFR) and Src are involved in the endocytosis and internalization of canalicular transporters in EIC ( Crocenzi et al, 2008 ; Boaglio et al, 2012 ; Andermatten et al, 2019 ). In the other hand, E 2 17G activates two GPR30-related signal pathway branches: adenylyl cyclase/PKA and insulin-like growth factor receptor-1 (IGF-1R)-phosphoinositide 3 kinase (PI3K)-Akt-MEK1/2-ERK1/2 signaling pathways, which can participate in endocytic internalization of transporters ( Crocenzi et al, 2008 ; Boaglio et al, 2010 ; Boaglio et al, 2012 ; Barosso et al, 2016 ).…”

Section: Pathophysiological Mechanisms Of Eicmentioning

confidence: 99%

The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives

Yang

Zhang

et al. 2021

Front. Pharmacol.

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Estrogens are steroid hormones with a wide range of biological activities. The excess of estrogens can lead to decreased bile flow, toxic bile acid (BA) accumulation, subsequently causing intrahepatic cholestasis. Estrogen-induced cholestasis (EIC) may have increased incidence during pregnancy, and within women taking oral contraception and postmenopausal hormone replacement therapy, and result in liver injury, preterm birth, meconium-stained amniotic fluid, and intrauterine fetal death in pregnant women. The main pathogenic mechanisms of EIC may include deregulation of BA synthetic or metabolic enzymes, and BA transporters. In addition, impaired cell membrane fluidity, inflammatory responses and change of hepatocyte tight junctions are also involved in the pathogenesis of EIC. In this article, we review the role of estrogens in intrahepatic cholestasis, and outlined the mechanisms of EIC, providing a greater understanding of this disease.

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Sphingosine 1-phosphate receptor 2/adenylyl cyclase/protein kinase A pathway is involved in taurolithocholate-induced internalization of Abcc2 in rats

Cited by 6 publications

References 53 publications

Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition

Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition

Molecular mechanisms of transporter regulation and their impairment in intrahepatic cholestasis

The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives

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