title: Evidence that actin depolymerization protects hippocampal neurons against excitotoxicity by stabilizing [Ca2+]i.
abstract: Calcium influx through glutamate receptors and voltage-dependent channels mediates an array of functional and structural responses in neurons. However, unrestrained Ca2+ influx can injure and kill neurons; a mechanism implicated in both acute and chronic neurodegenerative disorders. Data reported here indicate that depolymerization of actin filaments can stabilize intracellular free calcium levels ([Ca2+]i) and protect hippocampal neurons against excitotoxic injury. Studies with fluorescein-labeled phalloidin showed that cytochalasin D and glutamate each induced actin filament depolymerization. The microfilament-disrupting agent cytochalasin D protected cultured rat hippocampal neurons against glutamate toxicity, whereas the actin filament-stabilizing agent jasplakinolide potentiated glutamate toxicity. The microtubule-disrupting agent colchicine was ineffective in protecting neurons against glutamate toxicity. Cytochalasin D did not protect neurons against calcium ionophore toxicity or iron toxicity, indicating that its actions were not due to nonspecific effects on Ca2+ or free radical metabolism. Cytochalasin D markedly attenuated kainate-induced damage to hippocampus of adult rats, suggesting an excitoprotective role for actin depolymerization in vivo. Elevations of [Ca2+]i induced by glutamate were attenuated in cultured hippocampal neurons pretreated with cytochalasin D and potentiated in neurons pretreated with jasplakinolide. The [Ca2+]i response to a Ca2+ ionophore was unaffected by cytochalasin D, suggesting that actin depolymerization reduced Ca2+ influx through membrane channels. Taken together with previous patch clamp data, our findings suggest that depolymerization of actin in response to Ca2+ influx may serve as a feedback mechanism to attenuate potentially toxic levels of Ca2+ influx.
authors.affiliation: Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
authors.forename: K
authors.initials: K
authors.lastname: Furukawa
authors.forename: V L
authors.initials: VL
authors.lastname: Smith-Swintosky
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003572:Cytochalasins / Q000494:pharmacology; D047630:Depsipeptides; D004357:Drug Synergism; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D009994:Osmolar Concentration; D010456:Peptides, Cyclic / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D003572:Cytochalasins; D047630:Depsipeptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010456:Peptides, Cyclic; D011108:Polymers; C057531:jasplakinolide; D018698:Glutamic Acid; D002118:Calcium