Bellono Nicholas W, Escobar Iliana E, Lefkovith Ariel J, Marks Michael S, Oancea Elena
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, United States.
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, United States.
Elife. 2014 Dec 16;3:e04543. doi: 10.7554/eLife.04543.
Intracellular ion channels are essential regulators of organellar and cellular function, yet the molecular identity and physiological role of many of these channels remains elusive. In particular, no ion channel has been characterized in melanosomes, organelles that produce and store the major mammalian pigment melanin. Defects in melanosome function cause albinism, characterized by vision and pigmentation deficits, impaired retinal development, and increased susceptibility to skin and eye cancers. The most common form of albinism is caused by mutations in oculocutaneous albinism II (OCA2), a melanosome-specific transmembrane protein with unknown function. Here we used direct patch-clamp of skin and eye melanosomes to identify a novel chloride-selective anion conductance mediated by OCA2 and required for melanin production. Expression of OCA2 increases organelle pH, suggesting that the chloride channel might regulate melanin synthesis by modulating melanosome pH. Thus, a melanosomal anion channel that requires OCA2 is essential for skin and eye pigmentation.
细胞内离子通道是细胞器和细胞功能的重要调节因子，但其中许多通道的分子身份和生理作用仍不清楚。特别是，在黑素小体（产生和储存主要哺乳动物色素黑色素的细胞器）中尚未鉴定出离子通道。黑素小体功能缺陷会导致白化病，其特征是视力和色素沉着缺陷、视网膜发育受损以及皮肤和眼癌易感性增加。最常见的白化病形式是由眼皮肤白化病II型（OCA2）突变引起的，OCA2是一种功能未知的黑素小体特异性跨膜蛋白。在这里，我们使用皮肤和眼黑素小体的直接膜片钳技术，鉴定了一种由OCA2介导的新型氯离子选择性阴离子电导，这是黑色素产生所必需的。OCA2的表达会增加细胞器pH值，这表明氯离子通道可能通过调节黑素小体pH值来调节黑色素合成。因此，一种需要OCA2的黑素小体阴离子通道对皮肤和眼睛色素沉着至关重要。
