Cubilin and megalin co-localize in the neonatal inner ear.
Cubilin and megalin are multifunctional endocytotic receptors expressed in many absorptive epithelia. The receptors have separate functions but may act in concert in several tissues including the small intestine, the visceral yolk sac and the renal proximal tubule to perform significant physiological functions essential to homeostasis in the extracellular fluid compartments. Because of the importance of fluid homeostasis in the inner ear, we investigated the expression of cubilin and megalin in this structure. Furthermore, we examined the binding properties of 6 different aminoglycosides (AGs) to cubilin and compared the results to data obtained for megalin, which is a well-known receptor for AGs and other polybasic substances, including several ototoxic drugs. In the cochlea, immunohistochemical labelling for cubilin showed expression corresponding to the apical surface of the strial marginal cells, to epithelial cells at the spiral prominence and to epithelial cells of Reissner's membrane facing the cochlear duct. In the vestibular apparatus, positive labelling was found in dark cells of the utricle and those flanking the crista ampullaris of the semicircular canals. Exactly the same tissue distribution was found for megalin. These findings support the prevailing view that cubilin and megalin constitute a dual-receptor complex facilitating the function of each other. The physiological role of this receptor complex in the inner ear remains unknown, although several established ligands for both cubilin and megalin are present in the inner ear fluids. Receptor-ligand interaction analysis showed that all 6 AGs bind to both receptors and with approximately the same affinity. The results demonstrate a novel role for cubilin as a drug receptor for AGs and possibly other ototoxic substances.
Tauris
Jacob
J
Department of Otorhinolaryngology, Aarhus University Hospital, Aarhus, Denmark. tauris@dadlnet.dk
Christensen
Erik Ilsø
EI
Nykjaer
Anders
A
Jacobsen
Christian
C
Petersen
Claus Munck
CM
Ovesen
Therese
T
D000617:Aminoglycosides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D007758:Ear, Inner / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000737:chemistry / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance
D000617:Aminoglycosides; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor