TRPM1 forms ion channels associated with melanin content in melanocytes.
TRPM1 forms ion channels associated with melanin content in melanocytes.
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DOI：
10.1126/scisignal.2000146
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发表时间：
2009-05-12
影响因子：
7.3
通讯作者：
Clapham DE
中科院分区：
文献类型：
--
作者：
Oancea E;Vriens J;Brauchi S;Jun J;Splawski I;Clapham DE
TRPM1（melastatin）编码瞬时受体电位（TRP）离子通道 TRPM 家族的创始成员，首次通过其在高度转移性小鼠黑色素瘤细胞系中表达的减少而被识别。临床上，TRPM1 被用作人类黑色素瘤进展的预测因子，因为它在更具侵袭性的黑色素瘤中丰度较低。尽管 TRPM1 主要存在于黑色素生成细胞中，并且具有离子通道的分子结构，但其功能尚不清楚。在这里，我们描述了原代人新生儿表皮黑色素细胞和小鼠黑色素瘤细胞中的内源性电流，该电流通过针对 TRPM1 的 microRNA 的表达而消除。信使RNA分析表明，至少五种人类离子通道形成同种型TRPM1可能存在于黑色素细胞、黑色素瘤、大脑和视网膜中。其中两种亚型由高度保守的剪接变体编码，这些剪接变体是由先前未表征的外显子产生的。这两种剪接变体在人黑色素瘤细胞中的表达产生了类似于内源性 TRPM1 电流的离子电流。在黑色素瘤细胞中，TRPM1 普遍存在于高度动态的细胞内囊泡结构中。质膜 TRPM1 电流很小，这增加了它们的主要功能是在细胞内的可能性，或者仅限于质膜的特定区域。在新生儿人表皮黑色素细胞中，TRPM1 表达与黑色素含量相关。我们认为 TRPM1 是一种离子通道，其功能对正常黑素细胞色素沉着至关重要，因此是色素沉着疾病的潜在靶点。
TRPM1(melastatin), which encodes the founding member of the TRPM family of transient receptor potential (TRP) ion channels, was first identified by its reduced expression in a highly metastatic mouse melanoma cell line. Clinically, TRPM1 is used as a predictor of melanoma progression in humans because of its reduced abundance in more aggressive forms of melanoma. Although TRPM1 is found primarily in melanin-producing cells and has the molecular architecture of an ion channel, its function is unknown. Here we describe an endogenous current in primary human neonatal epidermal melanocytes and mouse melanoma cells that was abrogated by expression of microRNA directed against TRPM1. Messenger RNA analysis showed that at least five human ion channel–forming isoforms of TRPM1 could be present in melanocytes, melanoma, brain, and retina. Two of these isoforms are encoded by highly conserved splice variants that are generated by previously uncharacterized exons. Expression of these two splice variants in human melanoma cells generated an ionic current similar to endogenous TRPM1 current. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures. Plasma membrane TRPM1 currents are small, raising the possibility that their primary function is intracellular, or restricted to specific regions of the plasma membrane. In neonatal human epidermal melanocytes, TRPM1 expression correlates with melanin content. We propose that TRPM1 is an ion channel whose function is critical to normal melanocyte pigmentation and is thus a potential target for pigmentation disorders.