Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia
Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia
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DOI：
10.1073/pnas.0711027105
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发表时间：
2008-03-18
影响因子：
11.1
通讯作者：
Mykytyn, Kirk
中科院分区：
文献类型：
--
作者：
Berbari, Nicolas F.;Lewis, Jacqueline S.;Mykytyn, Kirk
初级纤毛是普遍存在的细胞附属物，提供重要但尚未充分理解的感觉和信号功能。睫状体功能障碍是许多人类遗传疾病的基础。然而，纤毛功能的确切缺陷和疾病的病理生理学基础仍不清楚。在这里，我们报告说，在人类睫状体疾病Bardet-Biedl综合征（BBS）的蛋白质破坏所需的G蛋白偶联受体的本地化的初级纤毛对中央神经元。我们证明了缺乏纤毛定位生长抑素受体3型（Sstr 3）和黑色素浓集激素受体1（Mchr 1）的小鼠缺乏Bbs 2或Bbs 4基因的神经元。由于Mchr 1参与调节摄食行为和BBS与hyperphagia诱导的肥胖症，我们的研究结果表明，改变信号引起的纤毛信号蛋白的错误定位的BBS表型。我们的研究结果还提供了将纤毛缺陷与肥胖联系起来的潜在分子机制。
Primary cilia are ubiquitous cellular appendages that provide important yet not well understood sensory and signaling functions. Ciliary dysfunction underlies numerous human genetic disorders. However, the precise defects in cilia function and the basis of disease pathophysiology remain unclear. Here, we report that the proteins disrupted in the human ciliary disorder Bardet-Biedl syndrome (BBS) are required for the localization of G protein-coupled receptors to primary cilia on central neurons. We demonstrate a lack of ciliary localization of somatostatin receptor type 3 (Sstr3) and melanin-concentrating hormone receptor 1 (Mchr1) in neurons from mice lacking the Bbs2 or Bbs4 gene. Because Mchr1 is involved in the regulation of feeding behavior and BBS is associated with hyperphagia-induced obesity, our results suggest that altered signaling caused by mislocalization of ciliary signaling proteins underlies the BBS phenotypes. Our results also provide a potential molecular mechanism to link cilia defects with obesity.