A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death

Wenyi Zhang, Xin Chu, Qin Tong, Joseph Y. Cheung, Kathleen Conrad, Kathryn Masker, Barbara A. Miller

Research output: Contribution to journalArticle

178 Scopus citations

Abstract

TRPM2 is a Ca2+-permeable channel that is activated by oxidative stress and confers susceptibility to cell death. Here, an isoform of TRPM2 was identified in normal human bone marrow that consists of the TRPM2 N terminus and the first two predicted transmembrane domains. Because of alternative splicing, a stop codon (TAG) is located at the splice junction between exons 16 and 17, resulting in deletion of the four C-terminal transmembrane domains, the putative calcium-permeable pore region, and the entire C terminus. This splice variant was found in other hematopoietic cells including human burst forming unit-erythroid-derived erythroblasts and TF-1 erythroleukemia cells. Endogenous expression of both the short form of TRPM2 (TRPM2-S) and the full length (TRPM2-L) was determined by reverse transcriptase-PCR, and localization of endogenous TRPM2 to the plasma membrane was demonstrated by confocal microscopy. Heterologous expression of TRPM2-S in HEK 293T cells demonstrated similar membrane localization as TRPM2-L, and coexpression of TRPM2-S did not alter the subcellular localization of TRPM2-L. The direct interaction of TRPM2-S with TRPM2-L was demonstrated with immunoprecipitation. H2O2 induced calcium influx through TRPM2-L expressed in 293T cells. Coexpression of TRPM2.S suppressed H2O2-induced calcium influx through TRPM2-L. Furthermore, expression of TRPM2-S inhibited susceptibility to cell death and onset of apoptosis induced by H2O2 in cells expressing TRPM2-L. These data demonstrate that TRPM2-S is an important physiologic isoform of TRPM2 and modulates channel activity and induction of cell death by oxidative stress through TRPM2-L.

Original languageEnglish (US)
Pages (from-to)16222-16229
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number18
DOIs
StatePublished - May 2 2003

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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