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Published online 29 November 2004. doi:10.1083/jcb.200409011
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 5, 915-924
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Article

Nontranscriptional modulation of intracellular Ca2+ signaling by ligand stimulated thyroid hormone receptor



Nuttawut Saelim1, Linu M. John2, Jun Wu1, Jeong Soon Park1, Yidong Bai1, Patricia Camacho2, and James D. Lechleiter1

1 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229
2 Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229

Correspondence to James D. Lechleiter: lechleiter{at}uthscsa.edu

Thyroid hormone 3,5,3'-tri-iodothyronine (T3) binds and activates thyroid hormone receptors (TRs). Here, we present evidence for a nontranscriptional regulation of Ca2+ signaling by T3-bound TRs. Treatment of Xenopus thyroid hormone receptor beta subtype A1 (xTRßA1) expressing oocytes with T3 for 10 min increased inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ wave periodicity. Coexpression of TRßA1 with retinoid X receptor did not enhance regulation. Deletion of the DNA binding domain and the nuclear localization signal of the TRßA1 eliminated transcriptional activity but did not affect the ability to regulate Ca2+ signaling. T3-bound TRßA1 regulation of Ca2+ signaling could be inhibited by ruthenium red treatment, suggesting that mitochondrial Ca2+ uptake was required for the mechanism of action. Both xTRßA1 and the homologous shortened form of rat TR{alpha}1 (rTR{alpha}{Delta}F1) localized to the mitochondria and increased O2 consumption, whereas the full-length rat TR{alpha}1 did neither. Furthermore, only T3-bound xTRßA1 and rTR{alpha}{Delta}F1 affected Ca2+ wave activity. We conclude that T3-bound mitochondrial targeted TRs acutely modulate IP3-mediated Ca2+ signaling by increasing mitochondrial metabolism independently of transcriptional activity.

N. Saelim's current address is: Dept. of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Pitsanulok, Thailand, 65000.

L.M. John's current address is: Pfizer, Inc., CVMD Biology, Groton, CT 06340.

Abbreviations used in this paper: ANT, adenine nucleotide translocator; DBD, DNA binding domain; {Delta}{Psi}, mitochondrial membrane potential; IP3, inositol 1,4,5-trisphosphate; MBS, modified barth's solution; O2, oxygen; pBOX, three amino acid sequence within the DNA binding domain that recognizes specific DNA binding sequences; RA, 9-cis retinoic acid; rTR{alpha}1, rat thyroid hormone receptor alpha subtype 1; rTR{alpha}{Delta}F1, shortened form of rat TR{alpha}1; Ru360, ruthenium 360; RXR, retinoid X receptor; SEAP, secreted placental alkaline phosphatase; T3, 3,5,3'-tri-iodothyronine; TMRE, tetramethylrhodamine ethyl ester; TR, thyroid receptor; TRE, thyroid hormone response element; xTRßA1, Xenopus thyroid hormone receptor beta subtype A1.


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