Altered store operated calcium entry increases cyclic 3',5'-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes (Articolo in rivista)

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  • Altered store operated calcium entry increases cyclic 3',5'-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes (Articolo in rivista) (literal)
Anno
  • 2012-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1002/hep.24723 (literal)
Alternative label
  • Spirli, Carlo; Locatelli, Luigi; Fiorotto, Romina; Morell, Carola M.; Fabris, Luca; Pozzan, Tullio; Strazzabosco, Mario (2012)
    Altered store operated calcium entry increases cyclic 3',5'-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes
    in Hepatology (Baltim. Md.)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Spirli, Carlo; Locatelli, Luigi; Fiorotto, Romina; Morell, Carola M.; Fabris, Luca; Pozzan, Tullio; Strazzabosco, Mario (literal)
Pagina inizio
  • 856 (literal)
Pagina fine
  • 868 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url
  • http://www.ncbi.nlm.nih.gov/pubmed/21987453 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 55 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#pagineTotali
  • 13 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 3 (literal)
Note
  • ISI Web of Science (WOS) (literal)
  • Scopu (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Yale University; Yale University; Osped Riuniti Bergamo; University of Padua; Consiglio Nazionale delle Ricerche (CNR); Venetian Inst Mol Med; University of Milano-Bicocca (literal)
Titolo
  • Altered store operated calcium entry increases cyclic 3',5'-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes (literal)
Abstract
  • Mutations in polycystins (PC1 or PC2/TRPP2) cause progressive polycystic liver disease (PLD). In PC2-defective mice, cyclic 3',5'-adenosine monophosphate/ protein kinase A (cAMP/PKA)-dependent activation of extracellular signal-regulated kinase/ mammalian target of rapamycin (ERK-mTOR) signaling stimulates cyst growth. We investigated the mechanisms connecting PC2 dysfunction to altered Ca2+ and cAMP production and inappropriate ERK signaling in PC2-defective cholangiocytes. Cystic cholangiocytes were isolated from PC2 conditional-KO (knockout) mice (Pkd2flox/-:pCxCreER (TM); hence, called Pkd2KO) and compared to cholangiocytes from wild-type mice (WT). Our results showed that, compared to WT cells, in PC2-defective cholangiocytes (Pkd2KO), cytoplasmic and ER-Ca2+ (measured with Fura-2 and Mag-Fluo4) levels are decreased and store-operated Ca2+ entry (SOCE) is inhibited, whereas the expression of Ca2+-sensor stromal interaction molecule 1 (STIM1) and store-operated Ca2+ channels (e.g., the Orai1 channel) are unchanged. In Pkd2KO cells, ER-Ca2+ depletion increases cAMP and PKA-dependent ERK1/2 activation and both are inhibited by STIM1 inhibitors or by silencing of adenylyl cyclase type 6 (AC6). Conclusion: These data suggest that PC2 plays a key role in SOCE activation and inhibits the STIM-dependent activation of AC6 by ER Ca2+ depletion. In PC2-defective cells, the interaction of STIM-1 with Orai channels is uncoupled, whereas coupling to AC6 is maximized. The resulting overproduction of cAMP, in turn, potently activates the PKA/ERK pathway. PLD, because of PC2 deficiency, represents the first example of human disease linked to the inappropriate activation of store-operated cAMP production. (HEPATOLOGY 2012) (literal)
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