This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Norman, A. W. Articles by Farach-Carson, M. C. Search for Related Content PubMed PubMed Citation Articles by Norman, A. W. Articles by Farach-Carson, M. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 1,25-DIHYDROXYCHOLECALCIFEROL

Comparison of 6-s-cis- and 6-s-trans-Locked Analogs of 1,25-Dihydroxyvitamin D₃ Indicates That the 6-s-cis Conformation Is Preferred for Rapid Nongenomic Biological Responses and That Neither 6-s-cis- nor 6-s-trans-Locked Analogs Are Preferred for Genomic Biological Responses

Division of Biomedical Sciences (A.W.N.), Departments of Biochemistry (A.W.N., J.E.B., M.C.D., M.C.F-C.) and Chemistry (W.H.O., M.W.H.), University of California, Riverside, California 92521,
Laboratorium voor Experimentele Geneeskunde en Endocrinologie (R.B., H.v.B.), Katholieke Universiteit Leuven, Leuven B-3000, Belgium,
Department of Basic Sciences (A.L.R., E.D., R.K., M.C.F-C.), University of Texas Dental Branch, Houston, Texas 77030

The hormone 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] generates biological responses via both genomic and rapid, nongenomic mechanisms. The genomic responses utilize signal transduction pathways linked to a nuclear receptor (VDR_nuc) for 1,25(OH)₂D₃, while the rapid responses are believed to utilize other signal transduction pathways that may be linked to a putative membrane receptor for 1,25(OH)₂D₃. The natural seco steroid is capable of facile rotation about its 6,7 single carbon bond, which permits generation of a continuum of potential ligand shapes extending from the 6-s-cis (steroid like) to the 6-s-trans (extended). To identify the shape of conformer(s) that can serve as agonists for the genomic and rapid biological responses, we measured multiple known agonist activities of two families of chemically synthesized analogs that were either locked in the 6-s-cis (6C) or 6-s-trans (6T) conformation. We found that 6T locked analogs were inactive or significantly less active than 1,25(OH)₂D₃ in both rapid responses (transcaltachia in perfused chick intestine, ⁴⁵Ca²⁺ influx in ROS 17/2.8 cells) and genomic (osteocalcin induction in MG-63 cells, differentiation of HL-60 cells, growth arrest of MCF-7 cells, promoter transfection in COS-7 cells) assays. In genomic assays, 6C locked analogs bound poorly to the VDR_nuc and were significantly less effective than 1,25(OH)₂D₃ in the same series of assays designed to measure genomic responses. In contrast, the 6C locked analogs were potent agonists of both rapid response pathways and had activities equivalent to the conformationally flexibile 1,25(OH)₂D₃; this represents the first demonstration that 6-s-cis locked analogs can function as agonists for vitamin D responses.

This article has been cited by other articles:

				M. T. Mizwicki and A. W. Norman The Vitamin D Sterol-Vitamin D Receptor Ensemble Model Offers Unique Insights into Both Genomic and Rapid-Response Signaling Sci. Signal., June 16, 2009; 2(75): re4 - re4. [Abstract] [Full Text] [PDF]

				R. Bouillon, G. Carmeliet, L. Verlinden, E. van Etten, A. Verstuyf, H. F. Luderer, L. Lieben, C. Mathieu, and M. Demay Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice Endocr. Rev., October 1, 2008; 29(6): 726 - 776. [Abstract] [Full Text] [PDF]

				A. R. Martineau, K. A. Wilkinson, S. M. Newton, R. A. Floto, A. W. Norman, K. Skolimowska, R. N. Davidson, O. E. Sorensen, B. Kampmann, C. J. Griffiths, et al. IFN-{gamma}- and TNF-Independent Vitamin D-Inducible Human Suppression of Mycobacteria: The Role of Cathelicidin LL-37 J. Immunol., June 1, 2007; 178(11): 7190 - 7198. [Abstract] [Full Text] [PDF]

				A. W. Norman Vitamin D Receptor: New Assignments for an Already Busy Receptor Endocrinology, December 1, 2006; 147(12): 5542 - 5548. [Abstract] [Full Text] [PDF]

				A. M. Vertino, C. M. Bula, J.-R. Chen, M. Almeida, L. Han, T. Bellido, S. Kousteni, A. W. Norman, and S. C. Manolagas Nongenotropic, Anti-Apoptotic Signaling of 1{alpha},25(OH)2-Vitamin D3 and Analogs through the Ligand Binding Domain of the Vitamin D Receptor in Osteoblasts and Osteocytes: MEDIATION BY Src, PHOSPHATIDYLINOSITOL 3-, AND JNK KINASES J. Biol. Chem., April 8, 2005; 280(14): 14130 - 14137. [Abstract] [Full Text] [PDF]

				J. A. Huhtakangas, C. J. Olivera, J. E. Bishop, L. P. Zanello, and A. W. Norman The Vitamin D Receptor Is Present in Caveolae-Enriched Plasma Membranes and Binds 1{alpha},25(OH)2-Vitamin D3 in Vivo and in Vitro Mol. Endocrinol., November 1, 2004; 18(11): 2660 - 2671. [Abstract] [Full Text] [PDF]

				M. T. Mizwicki, D. Keidel, C. M. Bula, J. E. Bishop, L. P. Zanello, J.-M. Wurtz, D. Moras, and A. W. Norman Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1{alpha},25(OH)2-vitamin D3 signaling PNAS, August 31, 2004; 101(35): 12876 - 12881. [Abstract] [Full Text] [PDF]

				L. Verlinden, A. Verstuyf, C. Verboven, G. Eelen, C. De Ranter, L.-J. Gao, Y.-J. Chen, I. Murad, M. Choi, K. Yamamoto, et al. Previtamin D3 with a trans-Fused Decalin CD-ring Has Pronounced Genomic Activity J. Biol. Chem., September 12, 2003; 278(37): 35476 - 35482. [Abstract] [Full Text] [PDF]

				R. M. LOSEL, E. FALKENSTEIN, M. FEURING, A. SCHULTZ, H.-C. TILLMANN, K. ROSSOL-HASEROTH, and M. WEHLING Nongenomic Steroid Action: Controversies, Questions, and Answers Physiol Rev, July 1, 2003; 83(3): 965 - 1016. [Abstract] [Full Text] [PDF]

				M. C. Rebsamen, J. Sun, A. W. Norman, and J. K. Liao 1{alpha},25-Dihydroxyvitamin D3 Induces Vascular Smooth Muscle Cell Migration via Activation of Phosphatidylinositol 3-Kinase Circ. Res., July 12, 2002; 91(1): 17 - 24. [Abstract] [Full Text] [PDF]

				Z. Schwartz, H. Ehland, V. L. Sylvia, D. Larsson, R. R. Hardin, V. Bingham, D. Lopez, D. D. Dean, and B. D. Boyan 1{alpha},25-Dihydroxyvitamin D3 and 24R,25-Dihydroxyvitamin D3 Modulate Growth Plate Chondrocyte Physiology via Protein Kinase C-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Endocrinology, July 1, 2002; 143(7): 2775 - 2786. [Abstract] [Full Text] [PDF]

				S. Ishizuka, D. Miura, K. Ozono, M. Chokki, H. Mimura, and A. W. Norman Antagonistic Actions in Vivo of (23S)-25-Dehydro-1{{alpha}}-Hydroxyvitamin D3-26,23-Lactone on Calcium Metabolism Induced by 1{{alpha}},25-Dihydroxyvitamin D3 Endocrinology, January 1, 2001; 142(1): 59 - 67. [Abstract] [Full Text] [PDF]

				E. Falkenstein, H.-C. Tillmann, M. Christ, M. Feuring, and M. Wehling Multiple Actions of Steroid Hormones---A Focus on Rapid, Nongenomic Effects Pharmacol. Rev., December 1, 2000; 52(4): 513 - 556. [Abstract] [Full Text] [PDF]

				M. Quack and C. Carlberg The Impact of Functional Vitamin D3 Receptor Conformations on DNA-Dependent Vitamin D3 Signaling Mol. Pharmacol., February 1, 2000; 57(2): 375 - 384. [Abstract] [Full Text]

				M. Kajikawa, H. Ishida, S. Fujimoto, E. Mukai, M. Nishimura, J. Fujita, Y. Tsuura, Y. Okamoto, A. W. Norman, and Y. Seino An Insulinotropic Effect of Vitamin D Analog with Increasing Intracellular Ca2+ Concentration in Pancreatic {beta}-Cells through Nongenomic Signal Transduction Endocrinology, October 1, 1999; 140(10): 4706 - 4712. [Abstract] [Full Text]

				D. M. Berry and K. A. Meckling-Gill Vitamin D Analogs, 20-Epi-22-Oxa-24a,26a,27a,-Trihomo-1{alpha},25(OH)2-Vitamin D3, 1,24(OH)2-22-Ene-24-Cyclopropyl-Vitamin D3 and 1{alpha},25(OH)2-Lumisterol3 Prime NB4 Leukemia Cells for Monocytic Differentiation via Nongenomic Signaling Pathways, Involving Calcium and Calpain Endocrinology, October 1, 1999; 140(10): 4779 - 4788. [Abstract] [Full Text]

				D. Miura, K. Manabe, K. Ozono, M. Saito, Q. Gao, A. W. Norman, and S. Ishizuka Antagonistic Action of Novel 1alpha ,25-Dihydroxyvitamin D3-26,23-lactone Analogs on Differentiation of Human Leukemia Cells (HL-60) Induced by 1alpha ,25-Dihydroxyvitamin D3 J. Biol. Chem., June 4, 1999; 274(23): 16392 - 16399. [Abstract] [Full Text] [PDF]

				S. H. Wang, R. J. Koenig, T. J. Giordano, A. Myc, N. W. Thompson, and J. R. Baker Jr. 1{alpha},25-Dihydroxyvitamin D3 Up-Regulates Bcl-2 Expression and Protects Normal Human Thyrocytes from Programmed Cell Death Endocrinology, April 1, 1999; 140(4): 1649 - 1656. [Abstract] [Full Text]

				J. B. Safran, W. T. Butler, and M. C. Farach-Carson Modulation of Osteopontin Post-translational State by 1,25-(OH)2-Vitamin D3. DEPENDENCE ON Ca2+ INFLUX J. Biol. Chem., November 6, 1998; 273(45): 29935 - 29941. [Abstract] [Full Text] [PDF]

				X. Song, J. E. Bishop, W. H. Okamura, and A. W. Norman Stimulation of Phosphorylation of Mitogen-Activated Protein Kinase by 1{alpha},25-Dihydroxyvitamin D3 in Promyelocytic NB4 Leukemia Cells: A Structure-Function Study Endocrinology, February 1, 1998; 139(2): 457 - 465. [Abstract] [Full Text] [PDF]