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

Thyroid hormone 3,5,3'-tri-iodothyronine (T-3) binds and activates thyroid hormone receptors (TRs). Here, we present evidence for a nontranscriptional regulation of Ca2+ signaling by T-3-bound TRs. Treatment of Xenopus thyroid hormone receptor beta subtype A1 (xTR(beta)A1) expressing oocytes with T-3 for 10 min increased inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ wave periodicity. Coexpression of TR(beta)A1 with retinoid X receptor did not enhance regulation. Deletion of the DNA binding domain and the nuclear localization signal of the TR(beta)A1 eliminated transcriptional activity but did not affect the ability to regulate Ca2+ signaling. T-3-bound TR(beta)A1 regulation of Ca2+ signaling could be inhibited by ruthenium red treatment, suggesting that mitochondrial Ca2+ uptake was required for the mechanism of action. Both xTR(beta)A1 and the homologous shortened form of rat TR(alpha)1 (rTRDelta/F1) localized to the mitochondria and increased O-2 consumption, whereas the full-length rat TR(alpha)1 did neither. Furthermore, only T3-bound xTR(beta)A1 and rTR(alpha)Delta/F1 affected Ca2+ wave activity. We conclude that T-3-bound mitochondrial targeted TRs acutely modulate IP3-mediated Ca2+ signaling by increasing mitochondrial metabolism independently of transcriptional activity.