Alterations in membrane caveolae and BKCa channel activity in skin fibroblasts in Smith-Lemli-Opitz syndrome

作者：Ren Gongyi; Jacob Robert F; Kaulin Yuri; Paul DiMuzio; Xie Yi; Mason R Preston; Tint G Stephen; Steiner Robert D; Roullet Jean Baptiste; Merkens Louise; Whitaker Menezes Diana; Frank Philippe G; Lisanti Michael P; Cox Robert H; Tulenko Thomas N^*

来源：Molecular Genetics and Metabolism, 2011, 104(3): 346-355.

DOI：10.1016/j.ymgme.2011.04.019

• 7-dehydrocholesterol
• beta-hydroxy-steroid-Delta(7)-reductase (DHCR7)
• Birth defects
• Caveolin-1
• Lipid rafts
• Membrane structure/function

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 50 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.

• 出版日期2011-11
• 单位河北医科大学