In addition, the channel also contributes to ischemic brain pathology. It has been shown that TRPM7 channel activity is up-regulated in oxygen glucose deprived cortical neurons and that knockdown of TRPM7 expression by RNA interference in cultured neurons and the hippocampus delayed anoxic cell death. To better understand the mechanism by which the channel contributes to the demise of cells under cellular stress, we characterized the cellular effects produced by increased TRPM7 channel activity employing HEK-293 cells as a model. Overexpression of the channel-kinase in HEK-293 cells produced cell rounding that was dependent upon the calcium-dependent protease m-calpain. More recently, we have shown that TRPM7 activates m-calpain through reactive oxygen species dependent activation of the stress-activated protein kinases p38 MAP kinase and c-Jun N-terminal kinase in HEK-293 cells. During the course of our investigation into the mechanism by which overexpression of TRPM7 caused loss of cell adhesion, we discovered that application of the non-specific lipoxygenase inhibitor NDGA attenuated cell rounding and loss of adhesion produced by influx of divalent cations through the channel. Electrophysiological measurements demonstrated that application of NDGA potently inhibited TRPM7 channel activity, suggesting that a lipoxygenase may be involved in regulating the channel. Lipoxygenases are a family of calciumdependent dioxygenases, including 5-lipoxygenase, 12lipoxygenase, and 15-lipoxygenase, that metabolize arachidonic acid to distinct biologically active fatty acid hydroperoxides, such as leukotrienes and hydroyeicosateraenoic acids. These metabolites take part in numerous cell processes, including inflammation, proliferation, cell invasion, angiogenesis, cell adhesion, and cell spreading. It is well known that lipid molecules modulate several members of the TRP family. In particular, products of lipoxygenase have been demonstrated to directly modulate TRPV1 channel activity. Activation of histamine and bradykinin receptors stimulates TRPV1 channel activity in a 12-LOX-dependent manner. Thus, our Trichostatin A discovery that NDGA blocked TRPM7 channel activity initially suggested to us that TRPM7 channel activity may be similarly controlled by a lipoxygenase. However, results from our experiments indicate that these compounds block TRPM7 channel activity independent of their actions on 5-LOX. Here we identify the 5-LOX inhibitors NDGA, AA861, and MK886 as potent blockers of the TRPM7 channel and demonstrate that depletion of TRPM7 channel activity by RNA interference or by treatment of cells with TRPM7 channel blockers reduces cell death caused by apoptotic stimuli. Stroke is the third leading cause of death in the United States as well as a major cause of disability. Considerable efforts have been spent on MK-0683 developing treatments for stroke, but they have been met with limited success. For example, the contribution of excitotoxicity mediated by glutamatergic NMDA receptors to ischemia-induced cell death is well appreciated, however, blockers of these receptors are not well tolerated and are only effective for a very short time following the onset of ischemia. Thus, the identification of new targets for pharmacological intervention in stroke is urgently needed. Two studies by the same group have highlighted the importance of TRPM7 to ischemic cell death.