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The Vitamin D Receptor Is Present in Caveolae-Enriched Plasma Membranes and Binds 1,25(OH)₂-Vitamin D₃ in Vivo and in Vitro

Department of Biochemistry, University of California, Riverside, California 92521

Address all correspondence and requests for reprints to: Anthony W. Norman, Distinguished Professor of Biochemistry and Biomedical Sciences, Department of Biochemistry, University of California, Riverside, Riverside, California 92521. E-mail: anthony.norman{at}ucr.edu.

The steroid hormone 1,25(OH)₂-vitamin D₃ (1,25D) regulates gene transcription through a nuclear receptor [vitamin D receptor (VDR)] and initiation of rapid cellular responses through a putative plasma membrane-associated receptor (VDR_mem). This study characterized the VDR_mem present in a caveolae-enriched membrane fraction (CMF), a site of accumulation of signal transduction agents. Saturable and specific [³H]-1,25D binding in vitro was found in CMF of chick, rat, and mouse intestine; mouse lung and kidney; and human NB4 leukemia and rat ROS 17/2.8 osteoblast-like cells; in all cases the 1,25D K_D binding dissociation constant = 1–3 nM. Our data collectively support the classical VDR being the VDR_mem in caveolae: 1) VDR antibody immunoreactivity was detected in CMF of all tissues tested; 2) competitive binding of [³H]-1,25D by eight analogs of 1,25D was significantly correlated between nuclei and CMF (r² = 0.95) but not between vitamin D binding protein (has a different ligand binding specificity) and CMF; 3) confocal immunofluorescence microscopy of ROS 17/2.8 cells showed VDR in close association with the caveolae marker protein, caveolin-1, in the plasma membrane region; 4) in vivo 1,25D pretreatment reduced in vitro [³H]-1,25D binding by 30% in chick and rat intestinal CMF demonstrating in vivo occupancy of the CMF receptor by 1,25D; and 5) comparison of [³H]-1,25D binding in VDR KO and WT mouse kidney tissue showed 85% reduction in VDR KO CMF and 95% reduction in VDR KO nuclear fraction. This study supports the presence of VDR as the 1,25D-binding protein associated with plasma membrane caveolae.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Coregulators:   CAV1

Ligands:   Calcitriol

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