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 journalArticle

15 Citations (Scopus)

Abstract

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
Volume46
Issue number7
DOIs
StatePublished - 2005

Fingerprint

Calcium-Sensing Receptors
Ceramides
Chemical activation
Apoptosis
Caspase 3
Phosphorylation
Cell death
Gi-Go GTP-Binding Protein alpha Subunits
Cells
Sphingomyelin Phosphodiesterase
Cell Death
JNK Mitogen-Activated Protein Kinases
DNA
Pertussis Toxin
G-Protein-Coupled Receptors
Cytochromes c
GTP-Binding Proteins
DNA Cleavage
Protein Kinases
HEK293 Cells

Keywords

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

ASJC Scopus subject areas

  • Endocrinology

Cite this

Wu, Z., Tandon, R., Ziembicki, J., Nagano, J., Hujer, K. M., Miller, R. T., & Huang, C. (2005). Role of ceramide in Ca2+-sensing receptor-induced apoptosis. Journal of Lipid Research, 46(7), 1396-1404. https://doi.org/10.1194/jlr.M500071-JLR200

Role of ceramide in Ca2+-sensing receptor-induced apoptosis. / Wu, Zhenzhen; Tandon, Rajnish; Ziembicki, Jenny; Nagano, Junko; Hujer, Kristine M.; Miller, R. Tyler; Huang, Chunfa.

In: Journal of Lipid Research, Vol. 46, No. 7, 2005, p. 1396-1404.

Research output: Contribution to journalArticle

Wu, Z, Tandon, R, Ziembicki, J, Nagano, J, Hujer, KM, Miller, RT & Huang, C 2005, 'Role of ceramide in Ca2+-sensing receptor-induced apoptosis', Journal of Lipid Research, vol. 46, no. 7, pp. 1396-1404. https://doi.org/10.1194/jlr.M500071-JLR200
Wu, Zhenzhen ; Tandon, Rajnish ; Ziembicki, Jenny ; Nagano, Junko ; Hujer, Kristine M. ; Miller, R. Tyler ; Huang, Chunfa. / Role of ceramide in Ca2+-sensing receptor-induced apoptosis. In: Journal of Lipid Research. 2005 ; Vol. 46, No. 7. pp. 1396-1404.
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