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.
Muallem
Shmuel
S
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. shmuel.muallem@utsouthwestern.edu
Moe
Orson W
OW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010375:Pedigree; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics*; D015499:Renal Tubular Transport, Inborn Errors / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000096:biosynthesis / Q000235:genetics; D013746:Tetany / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011498:Protein Precursors; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; C042652:epidermal growth factor precursor; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D008274:Magnesium; D000068818:Cetuximab