The Actin-Severing Protein Gelsolin Modulates Calcium Channel and NMDA Receptor Activities and Vulnerability to Excitotoxicity in Hippocampal Neurons

Abstract

Calcium influx through NMDA receptors and voltage-dependent calcium channels (VDCC) mediates an array of physiological processes in neurons and may also contribute to neuronal degeneration and death in neurodegenerative conditions such as stroke and severe epileptic seizures. Gelsolin is a Ca²⁺-activated actin-severing protein that is expressed in neurons, wherein it may mediate motility responses to Ca²⁺ influx. Primary hippocampal neurons cultured from mice lacking gelsolin exhibited decreased actin filament depolymerization and enhanced Ca²⁺ influx after exposure to glutamate. Whole-cell patch-clamp analyses showed that currents through NMDA receptors and VDCC were enhanced in hippocampal neurons lacking gelsolin, as a result of decreased current rundown; kainate-induced currents were similar in neurons containing and lacking gelsolin. Vulnerability of cultured hippocampal neurons to glutamate toxicity was greater in cells lacking gelsolin. Seizure-induced damage to hippocampal pyramidal neurons was exacerbated in adult gelsolin-deficient mice. These findings identify novel roles for gelsolin in controlling actin-mediated feedback regulation of Ca²⁺ influx and in neuronal injury responses. The data further suggest roles for gelsolin and the actin cytoskeleton in both physiological and pathophysiological events that involve activation of NMDA receptors and VDCC.