FIG. 3.

Perturbation of neural Ca²⁺ homeostasis under ischemic conditions. Neuronal and glial cell death is primarily mediated by oxidative stress and excess glutamate. Ca²⁺ entry through NMDAR mainly triggers the excitotoxic Ca²⁺ overload. As a result, calpains are activated, which inactivate by cleavage both NCX3 and PMCA. This precludes the capability to remove accumulated Ca²⁺. High [Ca²⁺]_i induces stimulation of nNOS, which leads to production of ONOO^•− and to the feedforward activation of TRPM7 currents. The decrease in [Ca²⁺] in the extracellular space disinhibits Ca²⁺-sensing channels, such as K_Ca3.1, leading to a further membrane depolarization. As a result of high [Ca²⁺]_i, excessive rise of intramitochondrial Ca²⁺ triggers the opening of the mPTP. Mitochondria also release Ca²⁺ via NCX_mito. This induces a depletion of ATP. Under ischemic conditions, the mode of operation of NCX_mito is reverted. Then, the NCX_mito acts as an influx pathway for Ca²⁺ into the mitochondrial matrix. ROS induce a high activity response of RyR2 and thus amplify the increase of [Ca²⁺]_i. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).