Figure 8.

Model of ER participation in axonal degeneration. Schematic representation of a neuron with soma and its axon. A mechanical injury (red bolt) isolates the axon and disrupts calcium equilibrium in the axon. Activation of voltage (discontinuous line to RyR) and metabotropic channels (discontinuous line to IP₃R) in the axonal plasma membrane can induce ER calcium release by RyaR and IP₃R. Calcium release from the ER is buffered by associated mitochondria (MITO; continuous black line). Crosstalk between RyaR and IP₃R (dotted line) might explain that inhibition of one ER channel might affect the release efficiency of the other one. Alternatively, the efficiency of calcium release can be compromised with only one functional channel. Mitochondrial calcium overload results in mPTP opening, which leads to calcium overload in the axon, increase in ROS generation (black line between mPTP and ROS; red arrow shows increase), and decrease in ATP production (black arrow from mPTP to ATP; red arrow shows decrease), which changes the direction of the Na²⁺/Ca²⁺ antiporter and additional calcium enters from the extracellular space (black arrow), which potentially induces cytoskeleton disintegration through calpain activation.