Two-pore channel 2 is required for soluble adenylyl cyclase-dependent regulation of melanosomal pH and melanin synthesis

IF 3.9 3区 医学 Q2 CELL BIOLOGY Pigment Cell & Melanoma Research Pub Date : 2024-06-06 DOI:10.1111/pcmr.13177
Dalee Zhou, Zuhal Eraslan, Dawson Miller, Isobel Taylor, Jaewon You, Samuel J. Grondin, Martha Vega, Prashiela Manga, Philip S. Goff, Elena V. Sviderskaya, Steven S. Gross, Qiuying Chen, Jonathan H. Zippin
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Abstract

Melanosomal pH is important for the synthesis of melanin as the rate-limiting enzyme, tyrosinase, is very pH-sensitive. The soluble adenylyl cyclase (sAC) signaling pathway was recently identified as a regulator of melanosomal pH in melanocytes; however, the melanosomal proteins critical for sAC-dependent regulation of melanosomal pH were undefined. We now systematically examine four well-characterized melanosomal membrane proteins to determine whether any of them are required for sAC-dependent regulation of melanosomal pH. We find that OA1, OCA2, and SLC45A2 are dispensable for sAC-dependent regulation of melanosomal pH. In contrast, TPC2 activity is required for sAC-dependent regulation of melanosomal pH and melanin synthesis. In addition, activation of TPC2 by NAADP-AM rescues melanosomal pH alkalinization and reduces melanin synthesis following pharmacologic or genetic inhibition of sAC signaling. These studies establish TPC2 as a critical melanosomal protein for sAC-dependent regulation of melanosomal pH and pigmentation.

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可溶性腺苷酸环化酶依赖性调节黑色素体pH值和黑色素合成需要双孔通道2。
黑色素体的pH值对黑色素的合成非常重要,因为限速酶酪氨酸酶对pH值非常敏感。可溶性腺苷酸环化酶(sAC)信号通路最近被确定为黑色素细胞中黑色素体pH值的调节因子;然而,依赖于sAC调节黑色素体pH值的黑色素体蛋白尚未确定。现在,我们系统地研究了四种特征明确的黑色素体膜蛋白,以确定它们中是否有任何一种是sAC依赖性调节黑色素体pH值所必需的。我们发现,OA1、OCA2 和 SLC45A2 在依赖 sAC 调节黑色素体 pH 的过程中是不可或缺的。相反,TPC2的活性则是依赖sAC调节黑色素体pH值和黑色素合成所必需的。此外,NAADP-AM 对 TPC2 的激活可在药物或基因抑制 sAC 信号传导后挽救黑色素体 pH 碱化并减少黑色素合成。这些研究确定了 TPC2 是依赖 sAC 调节黑色素体 pH 值和色素沉着的关键黑色素体蛋白。
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来源期刊
Pigment Cell & Melanoma Research
Pigment Cell & Melanoma Research 医学-皮肤病学
CiteScore
8.90
自引率
2.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Pigment Cell & Melanoma Researchpublishes manuscripts on all aspects of pigment cells including development, cell and molecular biology, genetics, diseases of pigment cells including melanoma. Papers that provide insights into the causes and progression of melanoma including the process of metastasis and invasion, proliferation, senescence, apoptosis or gene regulation are especially welcome, as are papers that use the melanocyte system to answer questions of general biological relevance. Papers that are purely descriptive or make only minor advances to our knowledge of pigment cells or melanoma in particular are not suitable for this journal. Keywords Pigment Cell & Melanoma Research, cell biology, melatonin, biochemistry, chemistry, comparative biology, dermatology, developmental biology, genetics, hormones, intracellular signalling, melanoma, molecular biology, ocular and extracutaneous melanin, pharmacology, photobiology, physics, pigmentary disorders
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