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

Saelim N, John LM, Wu J, Park JS, Bai Y, Camacho P, Lechleiter JD - J. Cell Biol. (2004)

Bottom Line: Coexpression of TRbetaA1 with retinoid X receptor did not enhance regulation.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.We conclude that T3-bound mitochondrial targeted TRs acutely modulate IP3-mediated Ca2+ signaling by increasing mitochondrial metabolism independently of transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 78229, USA.

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.

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T3 stimulation of oocytes expressing TRβA1 increases O2 consumption. (a) Plots of O2 levels in oocytes as labeled (n = 200 oocytes per group). (b) Histogram represents average change of O2 consumption rates (before and after T3 exposure) in control and xTRβA1 groups. Statistical significance is indicated by the asterisk (*; t test, P < 0.05).
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fig7: T3 stimulation of oocytes expressing TRβA1 increases O2 consumption. (a) Plots of O2 levels in oocytes as labeled (n = 200 oocytes per group). (b) Histogram represents average change of O2 consumption rates (before and after T3 exposure) in control and xTRβA1 groups. Statistical significance is indicated by the asterisk (*; t test, P < 0.05).

Mentions: Third, we directly test whether thyroid hormone receptor together with T3 stimulates mitochondrial respiration. Xenopus oocytes were injected with TRβA1 mRNA or water and incubated for 3 d. The rate of O2 consumption was measured as an indicator of respiration. 200 oocytes in each group were loaded into a 2-ml O2 probe chamber filled with modified barth's solution (MBS) solution. After 15 min of stabilization, the medium was exchanged with fresh MBS and O2 consumption was monitored for 30 min. The medium was exchanged a third time with MBS containing 100 nM T3 and O2 consumption was followed for another 30 min (Fig. 7, a and b). After this protocol, the rate of O2 consumption in water-injected oocytes after T3 exposure was 0.42 ± 0.25 nmol/min (n = 8). In contrast, the rate of O2 consumption in TRβA1-injected oocytes after T3 exposure was significantly increased to 1.68 ± 0.52 nmol/min (n = 4, P < 0.05). These data support the hypothesis that a T3 / TRβA1-mediated increase in mitochondrial respiration was responsible for the modulation of IP3-mediated Ca2+ wave activity.


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

Saelim N, John LM, Wu J, Park JS, Bai Y, Camacho P, Lechleiter JD - J. Cell Biol. (2004)

T3 stimulation of oocytes expressing TRβA1 increases O2 consumption. (a) Plots of O2 levels in oocytes as labeled (n = 200 oocytes per group). (b) Histogram represents average change of O2 consumption rates (before and after T3 exposure) in control and xTRβA1 groups. Statistical significance is indicated by the asterisk (*; t test, P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172460&req=5

fig7: T3 stimulation of oocytes expressing TRβA1 increases O2 consumption. (a) Plots of O2 levels in oocytes as labeled (n = 200 oocytes per group). (b) Histogram represents average change of O2 consumption rates (before and after T3 exposure) in control and xTRβA1 groups. Statistical significance is indicated by the asterisk (*; t test, P < 0.05).
Mentions: Third, we directly test whether thyroid hormone receptor together with T3 stimulates mitochondrial respiration. Xenopus oocytes were injected with TRβA1 mRNA or water and incubated for 3 d. The rate of O2 consumption was measured as an indicator of respiration. 200 oocytes in each group were loaded into a 2-ml O2 probe chamber filled with modified barth's solution (MBS) solution. After 15 min of stabilization, the medium was exchanged with fresh MBS and O2 consumption was monitored for 30 min. The medium was exchanged a third time with MBS containing 100 nM T3 and O2 consumption was followed for another 30 min (Fig. 7, a and b). After this protocol, the rate of O2 consumption in water-injected oocytes after T3 exposure was 0.42 ± 0.25 nmol/min (n = 8). In contrast, the rate of O2 consumption in TRβA1-injected oocytes after T3 exposure was significantly increased to 1.68 ± 0.52 nmol/min (n = 4, P < 0.05). These data support the hypothesis that a T3 / TRβA1-mediated increase in mitochondrial respiration was responsible for the modulation of IP3-mediated Ca2+ wave activity.

Bottom Line: Coexpression of TRbetaA1 with retinoid X receptor did not enhance regulation.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.We conclude that T3-bound mitochondrial targeted TRs acutely modulate IP3-mediated Ca2+ signaling by increasing mitochondrial metabolism independently of transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 78229, USA.

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.

Show MeSH
Related in: MedlinePlus