Nontranscriptional modulation of intracellular Ca(2+) 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 Ca(2+) signaling by T(3)-bound TRs. Treatment of Xenopus thyroid hormone receptor beta subtype A1 (xTR(β)A1) expressing oocytes with T(3) for 10 min increased inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) wave periodicity. Coexpression of TR(β)A1 with retinoid X receptor did not enhance regulation. Deletion of the DNA binding domain and the nuclear localization signal of the TR(β)A1 eliminated transcriptional activity but did not affect the ability to regulate Ca(2+) signaling. T(3)-bound TR(β)A1 regulation of Ca(2+) signaling could be inhibited by ruthenium red treatment, suggesting that mitochondrial Ca(2+) uptake was required for the mechanism of action. Both xTR(β)A1 and the homologous shortened form of rat TR(α)1 (rTR(α)ΔF1) localized to the mitochondria and increased O(2) consumption, whereas the full-length rat TR(α)1 did neither. Furthermore, only T(3)-bound xTR(β)A1 and rTR(α)ΔF1 affected Ca(2+) wave activity. We conclude that T(3)-bound mitochondrial targeted TRs acutely modulate IP(3)-mediated Ca(2+) signaling by increasing mitochondrial metabolism independently of transcriptional activity.