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J. Biol. Chem., Vol. 277, Issue 32, 28656-28662, August 9, 2002

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Thyroid Hormone Receptor ₁ Regulates Expression of the Na⁺/H⁺ Exchanger (NHE1)^*

Xiuju Li, Angelika J. Misik, Carmen V. Rieder, R. John Solaro^§, Anice Lowen, and Larry Fliegel^¶

From the  Department of Biochemistry, Faculty of Medicine, Canadian Institute of Health Research Membrane Protein Research Group, University of Alberta, Edmonton, Alberta T6G 2H7, Canada and the ^§ Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612-7342

In this paper we examine the role of thyroid hormone in regulating expression of the Na⁺/H⁺ exchanger. Thyroid hormone has been reported to regulate the activity of the Na⁺/H⁺ exchanger messenger RNA in some cell types. Treatment of cardiac myocytes with 3,5',3'-triiodothyronine results in an increased expression of Na⁺/H⁺ exchanger protein. Also, compared with euthyroid animals, hypothyroid rats express decreased amounts of the Na⁺/H⁺ exchanger protein. To examine the mechanisms involved in regulating expression of the Na⁺/H⁺ exchanger, we have characterized the regulation of a distal element of the NHE1 promoter by the thyroid hormone receptor. We have previously shown that a 1085/800 nucleotide (nt) region of the promoter is a modular element with a 841/800 nt activating element. Using electrophoretic mobility shift assay, we show that this element interacts with thyroid hormone receptor TR₁, a nuclear hormone receptor. The addition of exogenous TR increased transcriptional activity of the 841/800 nt element of the Na⁺/H⁺ exchanger promoter. We show that TR binds to a region on the 841/800 nt element that is near, but not identical, to the previously identified chicken ovalbumin upstream promoter transcription factor-binding site. Our results are the first demonstration that thyroid hormone and the thyroid hormone receptor TR₁ regulate expression of the Na⁺/H⁺ exchanger.

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