期刊
BIOCHEMISTRY
卷 49, 期 36, 页码 7847-7853出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi1006833
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资金
- Alzheimer's Association of America
- Uniformed Services University of the Health Sciences
On the basis of the consistent demonstrations that the A beta 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 A beta is initiated by calcium fluxes through A beta channels. We have found that a small four-histidine peptide, NAHis04, potently inhibits the A beta-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 A beta. PC12 cells loaded with Fura-2AM show a rapid increase in fluorescence and a rapid return to baseline after A beta 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 A beta 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 A beta pores in which the first part of the A beta 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 A beta residues Glu 11, His 13, and His 14.
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