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

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 (xTR_βA1) expressing oocytes with T₃ for 10 min increased inositol 1,4,5-trisphosphate (IP₃)-mediated Ca²⁺ wave periodicity. Coexpression of TR_βA1 with retinoid X receptor did not enhance regulation. Deletion of the DNA binding domain and the nuclear localization signal of the TR_βA1 eliminated transcriptional activity but did not affect the ability to regulate Ca²⁺ signaling. T₃-bound TR_βA1 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_βA1 and the homologous shortened form of rat TR_α1 (rTR_αΔF1) localized to the mitochondria and increased O₂ consumption, whereas the full-length rat TR_α1 did neither. Furthermore, only T₃-bound xTR_βA1 and rTR_αΔF1 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.