کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10833973 | 1065836 | 2011 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Alterations in membrane caveolae and BKCa channel activity in skin fibroblasts in Smith-Lemli-Opitz syndrome
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Alterations in membrane caveolae and BKCa channel activity in skin fibroblasts in Smith-Lemli-Opitz syndrome Alterations in membrane caveolae and BKCa channel activity in skin fibroblasts in Smith-Lemli-Opitz syndrome](/preview/png/10833973.png)
چکیده انگلیسی
The Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol synthesis caused by mutations in DHCR7 which encodes the final enzyme in the cholesterol synthesis pathway. The immediate precursor to cholesterol synthesis, 7-dehydrocholesterol (7-DHC) accumulates in the plasma and cells of SLOS patients which has led to the idea that the accumulation of abnormal sterols and/or reduction in cholesterol underlies the phenotypic abnormalities of SLOS. We tested the hypothesis that 7-DHC accumulates in membrane caveolae where it disturbs caveolar bilayer structure-function. Membrane caveolae from skin fibroblasts obtained from SLOS patients were isolated and found to accumulate 7-DHC. In caveolar-like model membranes containing 7-DHC, subtle, but complex alterations in intermolecular packing, lipid order and membrane width were observed. In addition, the BKCa K+ channel, which co-migrates with caveolin-1 in a membrane fraction enriched with cholesterol, was impaired in SLOS cells as reflected by reduced single channel conductance and a 50Â mV rightward shift in the channel activation voltage. In addition, a marked decrease in BKCa protein but not mRNA expression levels was seen suggesting post-translational alterations. Accompanying these changes was a reduction in caveolin-1 protein and mRNA levels, but membrane caveolar structure was not altered. These results are consistent with the hypothesis that 7-DHC accumulation in the caveolar membrane results in defective caveolar signaling. However, additional cellular alterations beyond mere changes associated with abnormal sterols in the membrane likely contribute to the pathogenesis of SLOS.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Genetics and Metabolism - Volume 104, Issue 3, November 2011, Pages 346-355
Journal: Molecular Genetics and Metabolism - Volume 104, Issue 3, November 2011, Pages 346-355
نویسندگان
Gongyi Ren, Robert F. Jacob, Yuri Kaulin, Paul, DiMuzio, Yi Xie, R. Preston Mason, G. Stephen Tint, Robert D. Steiner, Jean-Baptiste Roullet, Louise Merkens, Diana Whitaker-Menezes, Philippe G. Frank, Michael P. Lisanti, Robert H. Cox, Thomas N. Tulenko,