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

Abstract

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 (xTRβA1) expressing oocytes with T3 for 10 min increased inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ wave periodicity. Coexpression of TRβA1 with retinoid X receptor did not enhance regulation. Deletion of the DNA binding domain and the nuclear localization signal of the TRβA1 eliminated transcriptional activity but did not affect the ability to regulate Ca2+ signaling. T3-bound TRβA1 regulation of Ca2+ signaling could be inhibited by ruthenium red treatment, suggesting that mitochondrial Ca2+ uptake was required for the mechanism of action. Both xTRβA1 and the homologous shortened form of rat TRα1 (rTRαΔF1) localized to the mitochondria and increased O2 consumption, whereas the full-length rat TRα1 did neither. Furthermore, only T3-bound xTRβA1 and rTRαΔF1 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.