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Functional Vitamin D Receptor (VDR) in the T-Tubules of Cardiac Myocytes: VDR Knockout Cardiomyocyte Contractility

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Robert U. Simpson, Ph.D., Department of Pharmacology, 1301 MSRB III, 1150 West Medical Center Drive, University of Michigan Medical School, Ann Arbor, Michigan 48109. E-mail: robsim{at}umich.edu.

We have previously shown that the active form of vitamin D, 1,25 dihydroxyvitamin D3 [1,25(OH)₂D₃], has both genomic and rapid nongenomic effects in heart cells; however, the subcellular localization of the vitamin D receptor (VDR) in heart has not been studied. Here we show that in adult rat cardiac myocytes the VDR is primarily localized to the t-tubule. Using immunofluorescence and Western blot analysis, we show that the VDR is closely associated with known t-tubule proteins. Radioligand binding assays using ³H-labeled 1,25(OH)₂D₃ demonstrate that a t-tubule membrane fraction isolated from homogenized rat ventricles contains a 1,25(OH)₂D₃-binding activity similar to the classic VDR. For the first time, we show that cardiac myocytes isolated from VDR knockout mice show accelerated rates of contraction and relaxation as compared with wild type and that 1,25(OH)₂D₃ directly affects contractility in the wild-type but not the knockout cardiac myocyte. Moreover, we observed that acute (5 min) exposure to 1,25(OH)₂D₃ altered the rate of relaxation. A receptor localized to t-tubules in the heart is ideally positioned to exert an immediate effect on signal transduction mediators and ion channels. This novel discovery is fundamentally important in understanding 1,25(OH)₂D₃ signal transduction in heart cells and provides further evidence that the VDR plays a role in heart structure and function.