Cholesterol depletion reduces serotonin binding and signaling via human 5-HT_7(a) receptors

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• 作者：Benita Sjö ; gren ; Mark W. Hamblin and Per Svenningsson
• 刊名：European Journal of Pharmacology
• 出版年：2006
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：15 December 2006
• 卷：552
• 期：1-3
• 页码：1-10
• 文件大小：587 K

摘要

Lipids, including cholesterol, are critical components of the cell membrane where they are enriched in microdomains, lipid rafts, which organize and concentrate receptors and intracellular proteins involved in signal transduction. The present study examined the effects of cholesterol depletion on serotonin (5-HT) binding and signaling via 5-hydroxytryptamine₇ (5-HT₇) receptors in stably transfected HeLa cells. Immunohistochemical, ligand-binding and biotinylation experiments demonstrated that the studied cells expressed high levels of 5-HT₇ receptors at their surface with a pharmacological profile resembling 5-HT₇ receptors in native tissue. Depletion of cholesterol, by combined treatment with mevastatin, fumonisin B₁ and mevalonate or methyl-β-cyclodextrin (MβCD), caused highly significant reductions in the B_max values of [p>3p>H]5-HT- and [p>3p>H]-(R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol ([p>3p>H]SB269970)-binding to 5-HT₇ receptors. Cholesterol depletion also reduced the total level of 5-HT₇ receptor protein determined by Western blot analysis. None of the examined treatments affected the affinity of [p>3p>H]5-HT- or [p>3p>H]SB269970-binding to 5-HT₇ receptors. Treatment with serotonin caused strong inductions in the phosphorylation states of Serp>63p>-ATF-1 and Serp>133p>-CREB. These effects of serotonin on signal transduction were significantly counteracted by pre-treatment with cholesterol synthesis inhibitors. Altogether, the present study demonstrates that cholesterol depletion decreases binding of both agonist and antagonist radioligands to 5-HT₇ receptors and counteract 5-HT₇ receptor-mediated intracellular signaling.