Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
PLoS Genet. 2013;9(12):e1003983. doi: 10.1371/journal.pgen.1003983. Epub 2013 Dec 5.
Transcellular Mg(2+) transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg(2+) extrusion molecule. CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. CNNM4-knockout mice showed hypomagnesemia due to the intestinal malabsorption of magnesium, suggesting its role in Mg(2+) extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg(2+) by exchanging intracellular Mg(2+) with extracellular Na(+). Furthermore, CNNM4 mutations cause Jalili syndrome, characterized by recessive amelogenesis imperfecta with cone-rod dystrophy. CNNM4-knockout mice showed defective amelogenesis, and CNNM4 again localizes to the basolateral membrane of ameloblasts, the enamel-forming epithelial cells. Missense point mutations associated with the disease abolish the Mg(2+) extrusion activity. These results demonstrate the crucial importance of Mg(2+) extrusion by CNNM4 in organismal and topical regulation of magnesium.
细胞间的镁（Mg2+）转运穿过上皮细胞，包括顶端进入和基底外侧外排，这对于镁的体内平衡至关重要，但基底外侧外排的分子尚未被鉴定。在这里，我们表明 CNNM4 是基底外侧定位的 Mg2+外排分子。CNNM4 在肠道上皮细胞中强烈表达，并定位于其基底外侧膜。CNNM4 敲除小鼠由于镁的肠道吸收不良而出现低镁血症，这表明其在 Mg2+向体内内部的外排中起作用。成像分析表明，CNNM4 可以通过将细胞内的 Mg2+与细胞外的 Na+交换来外排 Mg2+。此外，CNNM4 突变导致 Jalili 综合征，其特征是隐性牙釉质不全伴锥杆营养不良。CNNM4 敲除小鼠表现出牙釉质形成缺陷，并且 CNNM4 再次定位于成釉细胞的基底外侧膜，即形成牙釉质的上皮细胞。与疾病相关的错义点突变会破坏 Mg2+外排活性。这些结果表明 CNNM4 在体内和局部调节镁方面的 Mg2+外排的重要性。
