A Novel TRPM2 Isoform Inhibits Calcium Influx and Susceptibility to Cell Death

Abstract

TRPM2 is a Ca 2؉ -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.

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

“…In the Gon-2 (dx22) allele, a conserved G427 is affected, which corresponds to G144 in TRPM6 and is located close to the critical S141 mutated in an HSH patient. In aggregate, experiments with TRPM6(S141L) strengthen the notion of a crucial role of the conserved N-terminal region for TRPM function as proposed for Gon-2 (West et al 2001), TRPM1 (Xu et al 2001), TRPM2 (Zhang et al 2003a) and TRPM4A/ TRPM4B isoforms (Launay et al 2002;Xu et al 2001).…”

Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation

“…12 Our results show a unique and previously unreported role for the TRPM2 protein, facilitating or promoting cell proliferation in cancer cells. The observation of a Ca 2 þ channel plays a non-Ca 2 þ transport function is surprising, but not completely new.…”

“…On the basis of the finding that TRPM2 is relocated in the nucleus of prostate cancer cells and the fact that TRPM2 has ADP-ribose pyrophosphatase activity, 6,12 we hypothesized that TRPM2 may decrease the level of poly ADP-ribose in the nucleus of cancer cells by catalyzing ADP-ribose to ribose 5-phosphate and AMP. 14 To test this hypothesis, we transfected (Lipofectamine, Invitrogen) siRNA-TRPM2 (40 nM) into PC-3 and BPH-1 cells for 72 h to knock down the expression of TRPM2 specifically.…”

“…10 ADP-ribose is a breakdown product of NAD þ , CD38, cADP-ribose, and protein de-acetylation. 4,11 As a bifunctional protein, TRPM2 protein contains a Nudix box in its C-terminus, 12 which is a common motif of enzymes that degrade nucleotide diphosphates in addition to serving as a binding site for ADP-ribose. 13 This study is designed to closely evaluate the role of TRPM2 in cell proliferation of prostate cancer cells.…”

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

“…Secondly, the electrophysiological properties seen following exposure to the specific TRPM2 messengers, NAD þ and ADPR, were very similar (Supplementary Figures S1 and S2) to those seen in TRPM2-expressing cell lines. [22][23][24]41 Moreover, a putative TRPM2 inhibitor, clotrimazole, 42 completely inhibited the ADPR-induced current (Supplementary Figure S2Ab).…”