TRPM2 and Stroke: Although it remains unknown how TRPM2 regulates the release of endogenous bilirubin from neurons and/or other peripheral cells and/or its clearance during stroke, the observation that D1066A mutation abolishes the neurotoxic component of the TRPM2 channel in ischemia-hypoxic brain injury raises the conceptual possibility of differentiating the physiological and pathological signaling embedded in the channel itself (Figure 8).