Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States.
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States.
Biochim Biophys Acta Mol Basis Dis. 2017 Oct;1863(10 Pt A):2496-2507. doi: 10.1016/j.bbadis.2017.03.001. Epub 2017 Mar 9.
The melanocortin-4 receptor (MC4R) plays a vital role in regulating energy homeostasis. Mutations in the MC4R cause early-onset severe obesity. The majority of loss of function MC4R mutants are retained intracellularly, many of which are not terminally misfolded and can be stabilized and targeted to the plasma membrane by different chaperones. Some of the mutants might be functional once coaxed to the cell surface. Molecular chaperones and chemical chaperones correct the misfolding of some mutant MC4Rs. However, their therapeutic application is very limited due to their non-specific mechanism of action and, for chemical chaperone, high dosage needed to be effective. Several pharmacological chaperones have been identified for the MC4R and Ipsen 5i and Ipsen 17 are the most potent and efficacious. Here we provide a comprehensive review on how different approaches have been applied to rescue misfolded MC4R mutants. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.
黑素皮质素 4 受体 (MC4R) 在调节能量平衡中起着至关重要的作用。MC4R 中的突变会导致早发性严重肥胖。大多数功能丧失的 MC4R 突变体被保留在细胞内，其中许多没有终末错误折叠，并且可以被不同的伴侣蛋白稳定并靶向到质膜。一些突变体一旦被诱导向细胞表面，可能具有功能。分子伴侣和化学伴侣可以纠正一些突变型 MC4R 的错误折叠。然而，由于它们非特异性的作用机制，以及化学伴侣需要高剂量才能有效，它们的治疗应用非常有限。已经确定了几种 MC4R 的药理学伴侣，其中 Ipsen 5i 和 Ipsen 17 是最有效和最有效的。在这里，我们提供了一个全面的综述，介绍了如何应用不同的方法来挽救错误折叠的 MC4R 突变体。本文是题为“黑素皮质素受体”的特刊的一部分-由 Ya-Xiong Tao 编辑。
