Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912.
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912.
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11508-11517. doi: 10.1073/pnas.1902825116. Epub 2019 May 16.
Opsins form a family of light-activated, retinal-dependent, G protein-coupled receptors (GPCRs) that serve a multitude of visual and nonvisual functions. Opsin 3 (OPN3 or encephalopsin), initially identified in the brain, remains one of the few members of the mammalian opsin family with unknown function and ambiguous light absorption properties. We recently discovered that OPN3 is highly expressed in human epidermal melanocytes (HEMs)-the skin cells that produce melanin. The melanin pigment is a critical defense against ultraviolet radiation (UVR), and its production is mediated by the Gαs-coupled melanocortin 1 receptor (MC1R). The physiological function and light sensitivity of OPN3 in melanocytes are yet to be determined. Here, we show that in HEMs, OPN3 acts as a negative regulator of melanin production by modulating the signaling of MC1R. OPN3 negatively regulates the cyclic adenosine monophosphate (cAMP) response evoked by MC1R via activation of the Gαi subunit of G proteins, thus decreasing cellular melanin levels. In addition to their functional relationship, OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures, and can form a physical complex. Remarkably, OPN3 can bind retinal, but does not mediate light-induced signaling in melanocytes. Our results identify a function for OPN3 in the regulation of the melanogenic pathway in epidermal melanocytes; we have revealed a light-independent function for the poorly characterized OPN3 and a pathway that greatly expands our understanding of melanocyte and skin physiology.
视蛋白是一类光激活的、视网膜依赖性的 G 蛋白偶联受体（GPCRs），它们具有多种视觉和非视觉功能。视蛋白 3（OPN3 或 encephalopsin）最初在大脑中被发现，仍然是哺乳动物视蛋白家族中为数不多的功能未知且光吸收特性模糊的成员之一。我们最近发现，OPN3 在人类表皮黑素细胞（产生黑色素的皮肤细胞）中高度表达。黑色素是抵御紫外线辐射（UVR）的关键防御物质，其产生由 Gαs 偶联的黑素皮质素 1 受体（MC1R）介导。OPN3 在黑素细胞中的生理功能和光敏感性尚未确定。在这里，我们表明在 HEMs 中，OPN3 通过调节 MC1R 的信号转导，作为黑色素生成的负调节剂。OPN3 通过激活 G 蛋白的 Gαi 亚基负调节 MC1R 引起的环腺苷酸（cAMP）反应，从而降低细胞内黑色素水平。除了它们的功能关系外，OPN3 和 MC1R 在质膜和细胞内结构中都有共定位，并且可以形成物理复合物。值得注意的是，OPN3 可以结合视黄醛，但不能在黑素细胞中介导光诱导的信号转导。我们的结果确定了 OPN3 在调节表皮黑素细胞黑素生成途径中的功能；我们揭示了 OPN3 的一种非依赖于光的功能，以及一条大大扩展了我们对黑素细胞和皮肤生理学理解的途径。
