Figure 7. Putative pathways for ROS-dependent enhancement of spontaneous exocytosis due to cholesterol depletion.

Decreases in cholesterol cause increases in the activity of membrane-bound NADPH oxidase (Nox), resulting in increased ROS production. Consequently, the amount of ROS is enhanced both in the extra- and in the intracellular spaces. This leads to stimulation of TRPV channels, thus admitting Ca²⁺ to the cytoplasm. The rise in intracellular Ca²⁺ may maintain spontaneous exocytosis at high levels. Ca²⁺ may activate phosphatase 2B (calcineurin, CaN), which has effects on proteins involved in the synaptic vesicle cycle, and may thus facilitate both recruitment of synaptic vesicles from pools for exocytosis and compensatory endocytosis. This pathway could be recruited along with others, as cholesterol depletion potentiated spontaneous exocytosis much less when any of the components of the NADPH oxidase–ROS–TRPV–Ca²⁺–calcineurin pathway were blocked.