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9.B.208 The Vitamin D3 Receptor (VDR) Family

The steroid hormone, vitamin D3, regulates gene transcription via at least two receptors and initiates putative rapid response systems at the plasma membrane. The vitamin D receptor (VDR) binds vitamin D3 and a second receptor, importin-4, imports the VDR-vitamin D3 complex into the nucleus via nuclear pores. Morrill et al. 2016 presented evidence that the Homo sapiens VDR homodimer contains two transmembrane (TM) helices ((327)E - D(342)), two TM 'half-helix' ((264)K N(276)), one or more large channels, and 16 cholesterol binding (CRAC/CARC) domains. The importin-4 monomer exhibits 3 pore- lining regions ((226)E - L(251); (768)V - G(783); (876)S - A(891)) and 16 CRAC/CARC domains. The MEMSAT algorithm indicated that VDR and importin-4 may not be restricted to cytoplasm and nucleus. The VDR homodimer TM helix-topology predicts insertion into the plasma membrane, with two 84 residue C-terminal regions being extracellular. Similarly, MEMSAT predicts importin-4 insertion into the plasma membrane with 226 residue extracellular N-terminal regions and 96 residue C-terminal extracellular loops; with the pore-lining regions contributing gated Ca2+ channels. The PoreWalker algorithm indicates that, of the 427 residues in each VDR monomer, 91 line the largest channel, including two vitamin D3 binding sites and residues from both the TM helix and 'half-helix'. Cholesterol-binding domains also extend into the channel within the ligand binding region. Programmed changes in bound cholesterol may regulate both membrane Ca2+ response systems and vitamin D3 uptake as well as receptor internalization by the endomembrane system culminating in uptake of the vitamin D3-VDR-importin-4 complex into the nucleus (Morrill et al. 2016).

References associated with 9.B.208 family:

Cheng, L., S. Zhang, F. Shang, Y. Ning, Z. Huang, R. He, J. Sun, and S. Dong. (2021). Emodin Improves Glucose and Lipid Metabolism Disorders in Obese Mice Activating Brown Adipose Tissue and Inducing Browning of White Adipose Tissue. Front Endocrinol (Lausanne) 12: 618037. 34040579
Geick, A., M. Eichelbaum, and O. Burk. (2001). Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 276: 14581-14587. 11297522
Grimm, S.L., S.M. Hartig, and D.P. Edwards. (2016). Progesterone Receptor Signaling Mechanisms. J. Mol. Biol. 428: 3831-3849. 27380738
Lehmann, J.M., D.D. McKee, M.A. Watson, T.M. Willson, J.T. Moore, and S.A. Kliewer. (1998). The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102: 1016-1023. 9727070
Li, Y., J.S. Ross-Viola, N.F. Shay, D.D. Moore, and M.L. Ricketts. (2009). Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr 139: 898-904. 19297428
Liu, X., J. Wang, M. Li, J. Qiu, X. Li, L. Qi, J. Liu, P. Liu, G. Xie, and X. Wang. (2023). Farnesoid X receptor is an important target for the treatment of disorders of bile acid and fatty acid metabolism in mice with nonalcoholic fatty liver disease combined with cholestasis. J Gastroenterol Hepatol. [Epub: Ahead of Print] 37415275
Luo, Y., X. Tan, X. Zhang, Y. Li, J. Huang, and Y. Deng. (2022). Effect of liver X receptor agonist TO901317 on cognitive function in APP/PS1 double transgenic mice with Alzheimers disease and the underlying mechanism. Zhong Nan Da Xue Xue Bao Yi Xue Ban 47: 1324-1331. 36411683
Morrill, G.A., A.B. Kostellow, and R.K. Gupta. (2016). The role of receptor topology in the vitamin D3 uptake and Ca2+ response systems. Biochem. Biophys. Res. Commun. 477: 834-840. 27369077
Wang, W., C. Zhang, A. Marimuthu, H.I. Krupka, M. Tabrizizad, R. Shelloe, U. Mehra, K. Eng, H. Nguyen, C. Settachatgul, B. Powell, M.V. Milburn, and B.L. West. (2005). The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1. Proc. Natl. Acad. Sci. USA 102: 7505-7510. 15897460
Watkins, R.E., J.M. Maglich, L.B. Moore, G.B. Wisely, S.M. Noble, P.R. Davis-Searles, M.H. Lambert, S.A. Kliewer, and M.R. Redinbo. (2003). 2.1 A crystal structure of human PXR in complex with the St. John''s wort compound hyperforin. Biochemistry 42: 1430-1438. 12578355