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Originally published In Press as doi:10.1074/jbc.M300298200 on February 19, 2003

J. Biol. Chem., Vol. 278, Issue 18, 16222-16229, May 2, 2003
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A Novel TRPM2 Isoform Inhibits Calcium Influx and Susceptibility to Cell Death*

Wenyi ZhangDagger , Xin ChuDagger , Qin TongDagger , Joseph Y. CheungDagger §, Kathleen ConradDagger , Kathryn MaskerDagger , and Barbara A. MillerDagger ||

From the Dagger  Henry Hood Research Program, The Sigfried and Janet Weis Center for Research and the Departments of § Medicine and  Pediatrics, The Geisinger Clinic, Danville, Pennsylvania 17822

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.

* This work was supported by National Institutes of Health Grants DK 46778 (to B. A. M.) and HL 58672 (to J. Y. C.) and grants from the Geisinger Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: The Henry Hood Research Program, The Sigfried and Janet Weis Center for Research, Geisinger Clinic, 100 North Academy Ave., Danville, PA 17822-2616. Tel.: 570-271-6675; Fax: 570-271-6701; E-mail: bamiller1@geisinger.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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