부산대학교 도서관

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1471-4159.2009.06278.x Byline: Myriam Gou-Fabregas, Ana Garcera, Stefka Mincheva, M. Jose Perez-Garcia (1), Joan X. Comella (2), Rosa M. Soler Keywords: calpain; intracellular calcium; membrane depolarization; motoneuron; neuronal survival Abstract: Abstract Intracellular calcium (Ca.sup.2+) concentration determines neuronal dependence on neurotrophic factors (NTFs) and susceptibility to cell death. Ca.sup.2+ overload induces neuronal death and the consequences are thought to be a probable cause of motoneuron (MN) degeneration in neurodegenerative diseases. In the present study, we show that membrane depolarization with elevated extracellular potassium (K.sup.+) was toxic to cultured embryonic mouse spinal cord MNs even in the presence of NTFs. Membrane depolarization induced an intracellular Ca.sup.2+ increase. Depolarization-induced toxicity and increased intracellular Ca.sup.2+ were blocked by treatment with antagonists to some of the voltage-gated Ca.sup.2+ channels (VGCCs), indicating that Ca.sup.2+ influx through these channels contributed to the toxic effect of depolarization. Ca.sup.2+ activates the calpains, cysteine proteases that degrade a variety of substrates, causing cell death. We investigated the functional involvement of calpain using a calpain inhibitor and calpain gene silencing. Pre-treatment of MNs with calpeptin (a cell-permeable calpain inhibitor) rescued MNs survival; calpain RNA interference had the same protective effect, indicating that endogenous calpain contributes to the cell death caused by membrane depolarization. These findings suggest that MNs are especially vulnerable to extracellular K.sup.+ concentration, which induces cell death by causing both intracellular Ca.sup.2+ increase and calpain activation. Article History: Received June 15, 2009; accepted July 4, 2009. Article note: Address correspondence and reprint requests to Rosa M Soler, Neuronal Signaling Unit, Department Ciencies Mediques Basiques, Facultat de Medicina, Universitat de Lleida-IRBLLEIDA, Montserrat Roig 2, 25008-Lleida, Spain. E-mail: rosa.soler@cmb.udl.es.