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GAIP, GIPC and Gi3 are Concentrated in Endocytic Compartments of Proximal Tubule Cells: Putative Role in Regulating Megalin’s Function

Xiaojing Lou^*, Tammie McQuistan^*, Robert A. Orlando and Marilyn Gist Farquhar^*

*Department of Cellular and Molecular Medicine and Pathology, University of California San Diego, La Jolla, California.

Correspondence to: Dr. Marilyn Gist Farquhar, Professor and Chair, Department of Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, Room 210, La Jolla, CA 92093-0651. Phone: 858-534-7711; Fax: 858-534-8549; E-mail: mfarquhar{at}ucsd.edu

ABSTRACT. Megalin is the most abundant endocytic receptor in the proximal tubule epithelium (PTE), where it is concentrated in clathrin-coated pits (CCPs) and vesicles in the brush border region. The heterotrimeric G protein alpha subunit, Gi3, has also been localized to the brush border region of PTE. By immunofluorescence GIPC and GAIP, components of G protein-mediated signaling pathways, are also concentrated in the brush border region of PTE and are present in megalin-expressing cell lines. By cell fractionation, these signaling molecules cosediment with megalin in brush border and microvillar fractions. GAIP is found by immunoelectron microscopy in CCPs, and GIPC is found in CCPs and apical tubules of endocytic compartments in the renal brush border. In precipitation assays, GST-GIPC specifically binds megalin. The concentration of Gi3, GIPC, and GAIP with megalin in endocytic compartments of the proximal tubule, where extensive endocytosis occurs, and the interaction between GIPC and the cytoplasmic tail of megalin suggest a model whereby G protein-mediated signaling may regulate megalin’s endocytic function and/or trafficking.

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