Mastoparan-induced apoptosis of cultured cerebellar granule neurons is initiated by calcium release from intracellular stores |
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Authors: | Sui-Zhen Lin Guang-Mei Yan Kimberly E Koch Steven M Paul Robert P Irwin |
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Institution: | aDepartments of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive (MS A-401), Indianapolis, IN 46202-5120, USA;bDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;cDepartment of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA;dLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA |
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Abstract: | We have recently reported that mastoparan, a peptide toxin isolated from wasp venom, induces apoptosis in cultured cerebellar granule neurons that can be blocked by cholera toxin, an activator of Gs. Measurements of intracellular free calcium concentration (Ca2+]i) reveal that mastoparan induces a dramatic elevation of Ca2+]i that is frequently followed by enhanced leakage of fura-2 out of the neurons, suggesting that this rise in Ca2+]i may be due to a more generalized change in membrane permeability. However, the mastoparan-induced initial elevation of Ca2+]i is maintained in the absence of extracellular Ca2+, suggesting that the rise of Ca2+]i is from intracellular stores. This conclusion is supported by the observation that depletion of Ca2+]i stores by pretreatment with either caffeine or thapsigargin attenuates both the rise in Ca2+]i and cell death induced by mastoparan. Phospholipase C (PLC) inhibitors, neomycin and U73122 block mastoparan-induced increases of Ca2+]i and protect against neuronal death. Pretreatment with cholera toxin, but not pertussis toxin, reduced the mastoparan-induced rise in Ca2+]i. Taken together, our data suggest that mastoparan initiates cell death in cerebellar granule neurons by inducing Ca2+ release from intracellular stores, probably via activation of PLC and IP3. A secondary or parallel process results in disruption of plasma membrane integrity and may be ultimately responsible for the death of these neurons by mastoparan. |
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Keywords: | Apoptosis Cell death Cerebellar granule neuron Intracellular calcium Mastoparan Cholera toxin Thapsigargin Caffeine |
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