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The unfolding story of megalin (gp330): now recognized as a drug receptor.

Editorial In this issue of The Journal Moestrup et al. (1) report that polybasic drugs such as aprotinin, aminoglycosides, and poly-myxin B are taken up by the endocytic receptor, megalin/gp330. Antibiotics such as gentamycin and polymyxin B are well known to be both nephrotoxic and ototoxic, but the mechanisms by which these drugs become concentrated in lysosomes of the kidney and ear to produce tissue damage remain unknown. This carefully executed study demonstrates that they bind to mega-lin/gp330 both in vitro and in vivo and are taken up by receptor-mediated endocytosis in clathrin-coated pits. Thus, Moestrup et al. (1) provide a clear explanation of the molecular mechanisms by which the kidney and probably also the ear take up and concentrate these toxic, polybasic drugs. At the same time the authors have added another dimension, a pathologic dimension, to the story of megalin (gp330) by showing that it serves as a drug receptor. What is megalin/gp330? gp330 (megalin) is one of the most abundant membrane proteins in the renal proximal tubule. It was originally identified as the target antigen of Heymann nephritis, a rat model of membranous glomerulonephritis (2, 3). Its location in clathrin-coated pits suggested from the beginning that gp330 is an endocytic receptor (3, 4). In addition to its expression in glomerular and proximal tubule epithelia, this receptor is expressed in a number of epithelia that are heavily engaged in receptor-mediated endocytosis, including type II cells of the lung and epithelial cells of the inner ear, epididymis, mammary gland, thyroid, parathyroid, yolk sac, and retina (5). Interest in this molecule was greatly enhanced when Raychowd-hury et al. (6) obtained and sequenced a partial cDNA clone which clearly established that gp330 is a member of the LDL receptor gene family (7). The complete amino acid sequence was obtained only recently (8), and this receptor was found to possess all the structural motifs characteristic of the LDL receptor family, including ligand binding, growth factor and EGF repeats, YWTD spacer regions, and the consensus (FX)NPXY endocytic internalization signal. Structurally it is quite similar to the LDL receptor related protein/a2-macroglobulin receptor (LRP), another LDL receptor family member. Based on its large size (517,715 mol wt) which proved to be larger than originally anticipated the name "megalin" was introduced as an alternative to gp330 (8). Ligands that bind to megalin/gp330. In the meantime the search for its ligands has identified a surprisingly diverse group …