Role of ceramide in Ca2+-sensing receptor-induced apoptosis

Zhenzhen Wu, Rajnish Tandon, Jenny Ziembicki, Junko Nagano, Kristine M. Hujer, R. Tyler Miller, Chunfa Huang

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Increased extracellular Ca2+ ([Ca2+]o) can damage tissues, but the molecular mechanisms by which this occurs are poorly defined. Using HEK 293 cell lines that stably overexpress the Ca 2+-sensing receptor (CaR), a G protein-coupled receptor, we demonstrate that activation of the CaR leads to apoptosis, which was determined by nuclear condensation, DNA fragmentation, caspase-3 activation, and increased cytosolic cytochrome c. This CaR-induced apoptotic pathway is initiated by CaR-induced accumulation of ceramide which plays an important role in inducing cell death signals by distinct G protein-independent signaling pathways. Pretreatment of wild-type CaR-expressing cells with pertussis toxin inhibited CaR-induced [3H]ceramide formation, c-Jun phosphorylation, and caspase-3 activation. The ceramide accumulation, c-Jun phosphorylation, and caspase-3 activation by the CaR can be abolished by sphingomyelinase and ceramide synthase inhibitors in different time frames. Cells that express a nonfunctional mutant CaR that were exposed to the same levels of [Ca 2+]o showed no evidence of activation of the apoptotic pathway. In conclusion, we report the involvement of the CaR in stimulating programmed cell death via a pathway involving GTP binding protein alpha subunit (Gαi)-dependent ceramide accumulation, activation of stress-activated protein kinase/c-Jun N-terminal kinase, c-Jun phosphorylation, caspase-3 activation, and DNA cleavage.

Original languageEnglish (US)
Pages (from-to)1396-1404
Number of pages9
JournalJournal of lipid research
Issue number7
StatePublished - 2005


  • G protein-coupled receptor
  • HEK 293 cell
  • Stress-activated protein kinase/c-Jun N-terminal kinase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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