title: 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 (xTRbetaA1) expressing oocytes with T3 for 10 min increased inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ wave periodicity. Coexpression of TRbetaA1 with retinoid X receptor did not enhance regulation. Deletion of the DNA binding domain and the nuclear localization signal of the TRbetaA1 eliminated transcriptional activity but did not affect the ability to regulate Ca2+ signaling. T3-bound TRbetaA1 regulation of Ca2+ signaling could be inhibited by ruthenium red treatment, suggesting that mitochondrial Ca2+ uptake was required for the mechanism of action. Both xTRbetaA1 and the homologous shortened form of rat TRalpha1 (rTRalphaDeltaF1) localized to the mitochondria and increased O2 consumption, whereas the full-length rat TRalpha1 did neither. Furthermore, only T3-bound xTRbetaA1 and rTRalphaDeltaF1 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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 78229, USA.
authors.forename: Nuttawut
authors.initials: N
authors.lastname: Saelim
authors.forename: Linu M
authors.initials: LM
authors.lastname: John
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Jeong Soon
authors.initials: JS
authors.lastname: Park
authors.forename: Yidong
authors.initials: Y
authors.lastname: Bai
authors.forename: Patricia
authors.initials: P
authors.lastname: Camacho
authors.forename: James D
authors.initials: JD
authors.lastname: Lechleiter
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D019069:Cell Respiration / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008024:Ligands; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D012430:Ruthenium Red; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium