Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK.
Eur J Pharmacol. 2011 Jun 11;660(1):171-80. doi: 10.1016/j.ejphar.2010.11.041. Epub 2011 Jan 3.
The melanocortin-2-receptor (MC(2) receptor), also known as the ACTH receptor, is a critical component of the hypothalamic-pituitary-adrenal axis. The importance of MC(2) receptor in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency, a potentially fatal disease characterised by isolated cortisol deficiency. MC(2)receptor mutations cause ~25% of cases. The discovery of a MC(2) receptor accessory protein MRAP, mutations of which account for ~15%-20% of familial glucocorticoid deficiency, has provided insight into MC(2) receptor trafficking and signalling. MRAP is essential for the functional expression of MC(2) receptor. MRAP2, a novel homolog of MRAP, can also facilitate MC(2) receptor cell surface expression and function. Like MRAP, MRAP2 is a small transmembrane domain glycoprotein capable of homodimerising. In addition, MRAP/MRAP2 can heterodimerise. The presence of MRAP2 adrenal expression suggests a possible role for MRAP2 in adrenal physiology, which has yet to be elucidated. Importantly, new data shows that the MRAPs can interact with all the other melanocortin receptors (MC(1,3,4,5) receptor). In contrast to MC(2) receptor, this interaction results in reduced melanocortin receptor surface expression and signalling. MRAP2 is predominantly expressed in brain. Hypothalamic expression has been demonstrated for both MRAP and MRAP2. The ability of MRAPs to modulate different members of the melanocortin receptor family in a bidirectional manner is intriguing. Furthermore, central nervous system expression of MRAPs points to a role beyond MC(2) receptor mediated adrenal steroidogenesis.
黑素皮质素 2 受体（MC（2）受体），也称为促肾上腺皮质激素受体，是下丘脑-垂体-肾上腺轴的关键组成部分。MC（2）受体在肾上腺生理学中的重要性体现在家族性糖皮质激素缺乏症中，这是一种潜在致命的疾病，其特征是孤立的皮质醇缺乏。MC（2）受体突变导致约 25%的病例。MC（2）受体辅助蛋白 MRAP 的发现，其突变约占家族性糖皮质激素缺乏症的 15%-20%，为 MC（2）受体的运输和信号转导提供了深入的了解。MRAP 是 MC（2）受体功能表达所必需的。MRAP2 是 MRAP 的一种新型同源物，也可以促进 MC（2）受体的细胞表面表达和功能。与 MRAP 一样，MRAP2 是一种能够形成同源二聚体的小跨膜域糖蛋白。此外，MRAP/MRAP2 可以异二聚化。MRAP2 在肾上腺中的表达表明其在肾上腺生理学中可能具有作用，但尚未阐明。重要的是，新数据表明 MRAPs 可以与所有其他黑素皮质素受体（MC（1、3、4、5）受体）相互作用。与 MC（2）受体不同，这种相互作用导致黑素皮质素受体表面表达和信号转导减少。MRAP2 主要在大脑中表达。已经证明 MRAP 和 MRAP2 在下丘脑中有表达。MRAPs 以双向方式调节黑素皮质素受体家族的不同成员的能力令人着迷。此外，MRAPs 在中枢神经系统中的表达表明其作用超出了 MC（2）受体介导的肾上腺类固醇生成。
