When EGF is offside, magnesium is wasted.
Our understanding of magnesium (Mg(2+)) regulation has recently been catapulted forward by the discovery of several disease loci for monogenic disorders of Mg(2+) homeostasis. In this issue of the JCI, Groenestege et al. report that their study of a rare inherited Mg(2+) wasting disorder in consanguineous kindred shows that EGF acts as an autocrine/paracrine magnesiotropic hormone (see the related article beginning on page 2260). EGF stimulates Mg(2+) reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane. These authors show that a point mutation in pro-EGF retains EGF secretion to the apical but not the basolateral membrane, disrupting this cascade and causing renal Mg(2+) wasting. This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology.
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. shmuel.muallem@utsouthwestern.edu
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