Polyhistidine Peptide Inhibitor of the Aβ Calcium Channel Potently Blocks the Aβ-Induced Calcium Response in Cells. Theoretical Modeling Suggests a Cooperative Binding Process
| Autor: | Yinon Shafrir, H. Robert Guy, Nelson Arispe, Juan Carlos Diaz, Stewart R. Durell |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.drug_class
chemistry.chemical_element Calcium channel blocker Calcium Models Biological PC12 Cells Biochemistry Calcium in biology Nitrendipine Alzheimer Disease mental disorders Calcium flux medicine Animals Humans Histidine Calcium metabolism Amyloid beta-Peptides Binding Sites Chemistry Calcium channel Cooperative binding Calcium Channel Blockers Peptide Fragments Rats nervous system diseases Biophysics Calcium Channels Fura-2 medicine.drug |
| Zdroj: | Biochemistry. 49:7847-7853 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi1006833 |
| Popis: | On the basis of the consistent demonstrations that the Abeta peptide of Alzheimer's disease forms calcium permeant channels in artificial membranes, we have proposed that the intracellular calcium increase observed in cells exposed to Abeta is initiated by calcium fluxes through Abeta channels. We have found that a small four-histidine peptide, NAHis04, potently inhibits the Abeta-induced calcium channel currents in artificial lipid membranes. Here we report that NaHis04 also potently blocks the intracellular calcium increase which is observed in cells exposed to Abeta. PC12 cells loaded with Fura-2AM show a rapid increase in fluorescence and a rapid return to baseline after Abeta is added to the medium. This fluorescence change occurs even when the medium contains nitrendipine, a voltage-gated calcium channel blocker, but fails to occur when application of Abeta is preceded by addition of NAHis04. Steep dose-response curves of the percentage of responding cells and cell viability show that NAHis04 inhibits in the micromolar range in an apparently cooperative manner. We have developed numerous models of Abeta pores in which the first part of the Abeta sequence forms a large beta-barrel ending at His 13. We have modeled how up to four NAHis04 peptides may block these types of pores by binding to side chains of Abeta residues Glu 11, His 13, and His 14. |
| Databáze: | OpenAIRE |
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