Abstract
Transcellular Mg2+ 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 Mg2+ 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 Mg2+ extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg2+ by exchanging intracellular Mg2+ 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 Mg2+ extrusion activity. These results demonstrate the crucial importance of Mg2+ extrusion by CNNM4 in organismal and topical regulation of magnesium.
Highlights
Magnesium is an essential element involved in a wide variety of biological activities
Mice genetically engineered not to express CNNM4, which localizes to the epithelial membrane facing to the inner parts of body, show hypomagnesemia due to the defect in magnesium absorption
These results indicate that CNNM4 mediates transcellular Mg2+ transport across the intestinal epithelia
Summary
Magnesium is an essential element involved in a wide variety of biological activities. CLDN16, encoding claudin-16/paracellin-1, and CLDN19, encoding claudin-19, are mutated in recessive familial hypomagnesemia with hypercalciuria and nephrocalcinosis [1,2] These genes are highly expressed in the thick ascending limb of Henle’s loop in the kidney and encode tight junction proteins, which form a cation-selective paracellular channel and drive the flux of Mg2+ between adjacent epithelial cells [3]. Another key molecule is TRPM6; mutations of TRPM6 cause recessive hypomagnesemia with secondary hypocalcemia [4,5]
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