Introduction
Megalin Receptor
Aminoglycosides
Steroid Hormones
Megalin Antagonists

Introduction

Megalin is a 600-kDa cell surface protein expressed on many epithelial surfaces of the human body including the renal proximal tubules and the cochlea of the inner ear (Figure 1, left).

Megalin is a member of the LDL receptor gene family, a group of multifunctional endocytic receptors that are responsible for cellular uptake of ligands from the extracellular space. The gene family currently consists of nine mammalian receptors, all of which share common structural motifs required for receptor-mediated endocytosis (Figure 1, right). Their extracellular domains are composed of clusters of complement-type repeats (the site of ligand binding) and epidermal growth factor homology domains (for intracellular release of ligands). Their cytoplasmic tails harbor motifs that regulate internalization and intracellular trafficking of the receptors.

Unlike the LDL receptor, whose primary role is to mediate cellular uptake of cholesterol-loaded lipoproteins, megalin has been shown to function as a promiscuous scavenger receptor primarily involved in uptake of proteins, lipid-soluble vitamins and steroid hormones into tissues that express the receptor (Table 1). Natural ligands of megalin include a long list of diverse proteins and chemical substances, many of which are bound with relatively low affinity.

Table 1. Megalin ligands

Vitamin-binding proteins Transcobalamin-vitamin B 12 Vitamin-D-binding protein Retinol-binding protein	Lipoproteins Apolipoprotein B Apolipoprotein E Apolipoprotein J/clusterin Apolipoprotein H	Immune- and stress related proteins Immunoglobulin light chains PAP-1 ß2 -microglobulin
Steroid hormone binding proteins Sex hormone binding protein-estrogens Androgen binding protein-androgens	Hormones and precursors Parathyroid hormone Insulin Epidermal growth factor Prolactin Thyroglobulin	Enzyme and enzyme inhibitors PAI-1 urokinase-PAI-1 tPA-PAI-1 Pro-urokinase Lipoprotein lipase Plasminogen ß-amylase ß1 -microglobulin Lysozyme
Other carrier proteins Albumin Lactoferrin Hemoglobin Odorant-binding protein Transthyretin	Drugs and toxins Aminoglycosides Polymyxin B Aprotinin Trichosanthin	Others RAP Ca 2+ Cytochrome c

Megalin interacts with its ligands through the extracellular domains of the receptor. Binding occurs either through complex protein-protein interactions (if the ligand is a protein), or through simple ionic interaction of positively charged substances with arrays of negatively charged amino acids in the complement type repeats (if the ligand is a chemical compound). Binding of lipid-soluble vitamins and steroid hormones to megalin are indirect and mediated though interaction of the receptor with specific carrier proteins that transport these substances in plasma.

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