Devi Sulochana, Kedlaya Rajendra, Maddodi Nityanand, Bhat Kumar M R, Weber Craig S, Valdivia Hector, Setaluri Vijayasaradhi
Dept. of Dermatology, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Am J Physiol Cell Physiol. 2009 Sep;297(3):C679-87. doi: 10.1152/ajpcell.00092.2009. Epub 2009 Jul 8.
Transient receptor potential melastatin (TRPM) is a subfamily of ion channels that are involved in sensing taste, ambient temperature, low pH, osmolarity, and chemical ligands. Melastatin 1/TRPM1, the founding member, was originally identified as melanoma metastasis suppressor based on its expression in normal pigment cells in the skin and the eye but not in aggressive, metastasis-competent melanomas. The role of TRPM1 and its regulation in normal melanocytes and in melanoma progression is not understood. Here, we studied the relationship of TRPM1 expression to growth and differentiation of human epidermal melanocytes. TRPM1 expression and intracellular Ca(2+) levels are significantly lower in rapidly proliferating melanocytes compared to the slow growing, differentiated melanocytes. We show that lentiviral short hairpin RNA (shRNA)-mediated knockdown of TRPM1 results in reduced intracellular Ca(2+) and decreased Ca(2+) uptake suggesting a role for TRPM1 in Ca(2+) homeostasis in melanocytes. TRPM1 knockdown also resulted in a decrease in tyrosinase activity and intracellular melanin pigment. Expression of the tumor suppressor p53 by transfection or induction of endogenous p53 by ultraviolet B radiation caused repression of TRPM1 expression accompanied by decrease in mobilization of intracellular Ca(2+) and uptake of extracellular Ca(2+). These data suggest a role for TRPM1-mediated Ca(2+) homeostasis, which is also regulated by ultraviolet B, in melanogenesis.
瞬时受体电位褪黑素（TRPM）是离子通道的一个亚家族，参与味觉、环境温度、低pH值、渗透压和化学配体的感知。褪黑素1/TRPM1作为该家族的首个成员，最初是基于其在皮肤和眼睛的正常色素细胞中表达，而在具有侵袭性、有转移能力的黑色素瘤中不表达，被鉴定为黑色素瘤转移抑制因子。TRPM1在正常黑素细胞以及黑色素瘤进展中的作用及其调控机制尚不清楚。在此，我们研究了TRPM1表达与人类表皮黑素细胞生长和分化的关系。与生长缓慢、分化的黑素细胞相比，快速增殖的黑素细胞中TRPM1表达和细胞内Ca²⁺水平显著降低。我们发现，慢病毒短发夹RNA（shRNA）介导的TRPM1敲低导致细胞内Ca²⁺减少和Ca²⁺摄取降低，提示TRPM1在黑素细胞Ca²⁺稳态中发挥作用。TRPM1敲低还导致酪氨酸酶活性和细胞内黑色素含量降低。通过转染表达肿瘤抑制因子p53或用紫外线B辐射诱导内源性p53表达，会导致TRPM1表达受到抑制，同时细胞内Ca²⁺动员和细胞外Ca²⁺摄取减少。这些数据表明TRPM1介导的Ca²⁺稳态在黑素生成中发挥作用，且该稳态也受紫外线B的调控。
