Kifor Olga, Kifor Imre, Moore Francis D, Butters Robert R, Cantor Thomas, Gao Ping, Brown Edward M
Endocrine-Hypertension Division and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Clin Endocrinol Metab. 2003 Sep;88(9):4455-64. doi: 10.1210/jc.2002-021427.
Caveolins are key components of caveolae membranes. The calcium-sensing receptor (CaR) resides within caveolin-rich membrane domains in bovine parathyroid (PT) cells. Recent studies reported reduced CaR expression, and abnormal calcium-sensing in PT tumors. To examine this altered CaR signaling, we investigated ERK activation after CaR stimulation in human and bovine PT cells. In freshly prepared bovine PT cells, high extracellular calcium (Ca(2+)(0)) stimulates ERK1/2 phosphorylation, and activated ERK1/2 colocalizes with caveolin-1 at the plasma membrane but fails to translocate to the nucleus, and cell proliferation is low. In cultured bovine PT cells, CaR and caveolin-1 levels are reduced; activated ERK1/2 localizes in the cell periphery at 10 min and in the perinuclear and nuclear regions at 60 min after exposure to high Ca(2+)(0), and cell proliferation is increased. In PT cells from adenomas, there are high levels of caveolin-2, variably reduced caveolin-1, and hyperactivation of ERK1/2, which colocalizes with caveolin-1 in some cells, but localizes in the cytosol and nucleus in others. Finally, caveolin-1 negative human PT cells exhibit reduced suppressibility of PTH secretion by high Ca(2+)(0). Thus, CaR and caveolin-1 colocalize in PT cells, and reduced levels of caveolin-1 could participate in the abnormal cellular function and proliferation of cultured bovine PT cells and PT adenomas.
小窝蛋白是小窝膜的关键组成部分。钙敏感受体（CaR）存在于牛甲状旁腺（PT）细胞富含小窝蛋白的膜结构域中。最近的研究报道了PT肿瘤中CaR表达降低以及钙感知异常。为了研究这种改变的CaR信号传导，我们在人和牛的PT细胞中研究了CaR刺激后ERK的激活情况。在新鲜制备的牛PT细胞中, 高细胞外钙（Ca(2+)(0)）刺激ERK1/2磷酸化，激活的ERK1/2与小窝蛋白-1在质膜共定位，但不能转位至细胞核，且细胞增殖率较低。在培养的牛PT细胞中，CaR和小窝蛋白-1水平降低；暴露于高Ca(2+)(0)后，激活的ERK1/2在10分钟时位于细胞周边，60分钟时位于核周和核区域，且细胞增殖增加。在腺瘤的PT细胞中，小窝蛋白-2水平较高，小窝蛋白-1水平可变降低，ERK1/2过度激活，其在一些细胞中与小窝蛋白-1共定位，但在其他细胞中位于细胞质和细胞核中。最后，小窝蛋白-1阴性的人PT细胞对高Ca(2+)(0)抑制甲状旁腺激素分泌的能力降低。因此，CaR和小窝蛋白-1在PT细胞中共定位，小窝蛋白-1水平降低可能参与了培养的牛PT细胞和PT腺瘤的异常细胞功能及增殖。
