Figure 9.

A model showing how gelsolin activation leading to dynamic changes in the actin cytoskeleton may modify tissue injury in cerebral ischemia. Brain ischemia promotes neuronal depolarization, which activates VDCC directly and NMDA channels by the release of glutamate. Activation of both channels mediates intracellular Ca²⁺ influx, which activates various cell death–promoting intracellular enzymes. Ca²⁺ also activates the actin-severing protein gelsolin, which in turn mediates dynamic changes (net depolymerization) in the actin filament network. This actin remodeling event leads to channel rundown, inactivation, and stabilization of [Ca²⁺]_i. Thus, gelsolin acts as an intracellular Ca²⁺ sensor, negatively regulating Ca²⁺ influx and thereby protecting against neuronal dysfunction and death. Cyto D, through similar effects on the actin cytoskeleton, also exhibits neuroprotective effects VDCC, voltage-dependent Ca²⁺ channels; NMDA, N-methyl-D-aspartate.