Expression of Cav1.3 calcium channel in the human and mouse colon: Posttranscriptional inhibition by IFNγ

Vijayababu M. Radhakrishnan, Maryam M. Gilpatrick, Nour Alhoda Parsa, Pawel R Kiela, Fayez K Ghishan

Research output: Contribution to journalArticle

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Abstract

It has been hypothesized that apically expressed L-type Ca2+ channel Cav1.3 (encoded by CACNA1D gene) contributes toward an alternative TRPV6-independent route of intestinal epithelial Ca2+ absorption, especially during digestion when high luminal concentration of Ca2+ and other nutrients limit TRPV6 contribution. We and others have implicated altered expression and activity of key mediators of intestinal and renal Ca2+ (re)absorption as contributors to negative systemic Ca2+ balance and bone loss in intestinal inflammation. Here, we investigated the effects of experimental colitis and related inflammatory mediators on colonic Cav1.3 expression. We confirmed Cav1.3 expression within the segments of the mouse and human gastrointestinal tract. Consistent with available microarray data (GEO database) from inflammatory bowel disease (IBD) patients, mouse colonic expression of Cav1.3 was significantly reduced in trinitrobenzene sulfonic acid (TNBS) colitis. In vitro, IFNγ most potently reduced Cav1.3 expression. We reproduced these findings in vivo with wild-type and Stat1-/- mice injected with IFNγ. The observed effect in Stat1-/- suggested a noncanonical transcriptional repression or a posttranscriptional mechanism. In support of the latter, we observed no effect on the cloned Cav1.3 gene promoter activity and accelerated Cav1.3 mRNA decay rate in IFNγ-treated HCT116 cells. While the relative contribution of Cav1.3 to intestinal Ca2+absorption and its value as a therapeutic target remain to be established, we postulate that Cav1.3 downregulation in IBD may contribute to the negative systemic Ca2+ balance, to increased bone resorption, and to reduced bone mineral density in IBD patients.

Original languageEnglish (US)
Pages (from-to)G77-G84
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume312
Issue number1
DOIs
StatePublished - Dec 8 2016

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Keywords

  • Calcium absorption
  • Calcium channel
  • Inflammation
  • Interferon
  • Intestine

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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