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首页> 外文期刊>Cellular Signalling >Lipid rafts constrain basal alpha(1A)-adrenergic receptor signaling by maintaining receptor in an inactive conformation
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Lipid rafts constrain basal alpha(1A)-adrenergic receptor signaling by maintaining receptor in an inactive conformation

机译：脂质筏通过维持受体处于非活性构象来限制基底α（1A）-肾上腺素能受体的信号传导

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摘要

We have reported that the alpha(1A)-adrenergic receptor (alpha(1A)AR) in rat-1 fibroblasts is a lipid raft protein. Here we examined whether disrupting lipid rafts by methyl-beta-cyclodextrin (MCD) sequestration of cholesterol affects alpha(1A)AR signaling. Unexpectedly, MCD increased alpha(1A)AR-dependent basal inositol phosphate formation and p38 mitogen-activated protein kinase activation in a cholesterol-dependent manner. It also initiated internalization of surface alpha(1A)AR, which was partially blocked by receptor inhibition. Binding assays revealed MCD-mediated increases in receptor agonist affinity as well as reciprocal decreases in inverse agonist affinity, a behavior that is usually interpreted as a shift toward the active receptor conformation. In untreated cells a fraction of the receptor was found to be present in preassociated receptor/G protein complexes, which rapidly dissociate upon receptor stimulation. Consistent with MCD-induced signaling, raft disruption resulted in an increase in receptor/G protein complexes. These results strongly suggest that lipid rafts constrain basal alpha(1A)AR activity; however, preassembled receptor/G protein complexes could still provide a mechanism for accelerating alpha(1A)AR signaling following stimulation.
机译：我们已经报告大鼠1成纤维细胞中的alpha（1A）-肾上腺素能受体（alpha（1A）AR）是一种脂筏蛋白。在这里，我们检查了通过甲基-β-环糊精（MCD）隔离胆固醇破坏脂筏是否影响alpha（1A）AR信号传导。出乎意料的是，MCD以胆固醇依赖的方式增加了alpha（1A）AR依赖的基础肌醇磷酸的形成和p38丝裂原激活的蛋白激酶的激活。它还启动了表面alpha（1A）AR的内部化，该表面被受体抑制部分阻止。结合测定揭示了MCD介导的受体激动剂亲和力增加以及反向激动剂亲和力的倒数降低，这种行为通常被解释为向活性受体构象的转变。在未处理的细胞中，发现一部分受体存在于预缔合的受体/ G蛋白复合物中，该复合物在受体刺激后迅速解离。与MCD诱导的信号传导一致，木筏破坏导致受体/ G蛋白复合物增加。这些结果强烈表明脂质筏约束基底α（1A）AR活性;但是，预组装的受体/ G蛋白复合物仍可提供刺激后加速alpha（1A）AR信号传导的机制。

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