Yanik Tulin, Dominguez Geraldina, Kuhar Michael J, Del Giudice Emanuele M, Loh Y Peng
Section on Cellular Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4480, USA.
Endocrinology. 2006 Jan;147(1):39-43. doi: 10.1210/en.2005-0812. Epub 2005 Oct 6.
Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic neuropeptide synthesized in the hypothalamus. A Leu34Phe missense mutation in proCART has been found in an obese family in humans. Here we show that humans bearing the Leu34Phe mutation in proCART have severely diminished levels of bioactive CART, but elevated amounts of partially processed proCART in their serum. Expression of wild-type proCART in AtT-20 cells showed that it was sorted to the regulated secretory pathway, a necessity for proper processing to bioactive CART. However, expressed Leu34Phe proCART was missorted, poorly processed, and secreted constitutively. The defective intracellular sorting of Leu34Phe proCART would account for the reduced levels of bioactive CART in affected humans. These results suggest that the obesity observed in humans bearing the Leu34Phe mutation could be due to a putative deficiency in hypothalamic bioactive CART.
可卡因和苯丙胺调节转录肽（CART）是一种在下丘脑中合成的厌食性神经肽。在一个人类肥胖家族中发现了前CART中的Leu34Phe错义突变。在此我们表明，携带前CART中Leu34Phe突变的人类生物活性CART水平严重降低，但其血清中部分加工的前CART量升高。野生型前CART在AtT - 20细胞中的表达表明，它被分选到调节性分泌途径，这是正确加工成生物活性CART的必要条件。然而，表达的Leu34Phe前CART分选错误，加工不良，并组成性分泌。Leu34Phe前CART细胞内分选缺陷可解释受影响人类生物活性CART水平降低的原因。这些结果表明，携带Leu34Phe突变的人类中观察到的肥胖可能是由于下丘脑生物活性CART的假定缺乏所致。
