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Administration of Triiodo-l-thyronine into Dorsal Hippocampus Alters Phosphorylation of Akt, Mammalian Target of Rapamycin, p70S6 Kinase and 4E-BP1 in Rats

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Abstract

Thyroid hormones play critical roles in brain functions. The underlying mechanisms remain unknown but classical regulation of gene expression through binding to nuclear thyroid hormone receptors has been widely implicated. Evidence has also accumulated suggesting that thyroid hormone can exert effects through non-classical mechanisms involving activation of signal transduction pathways. Whether thyroid hormone can activate signal transduction pathways in the brain is not fully understood. In this study, we administrated 3,5,3′-triiodo-l-thyronine (T3) into rat dorsal hippocampus and determined the phosphorylation of Akt and its downstream targets, mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6k) and the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) signaling molecules. T3 caused specific rapid and persistent activation of phosphatidylinositol 3-kinase (PI3K)/Akt-mTOR signaling pathway, which was mediated by thyroid hormone receptors. Furthermore, the rapid action of T3 did not require protein or RNA synthesis, whereas, the persistent action of T3 was translational and transcriptional activities-dependent. These findings indicated that activation of PI3K/Akt-mTOR signaling pathway provides a new molecular mechanism for thyroid hormone actions in the hippocampus and this new mechanism may contribute to some effects of thyroid hormones in the central nervous system.

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Abbreviations

acti D:

Actinomycin D

aCSF:

Artificial cerebrospinal fluid

ANOVA:

Analysis of variance

CHX:

Cycloheximide

DMSO:

Dimethyl sulfoxide

DTT:

Dithiothreitol

ECL:

Enhanced chemiluminescence

4E-BP1:

Eukaryotic initiation factor 4E-binding protein 1

eIF4E:

Eukaryotic initiation factor 4E

ERK:

Extracellular signal regulated kinase

HRP:

Horseradish peroxidase

LTP:

Long-term potentiation

MAPK:

Mitogen-activated protein kinase

mTOR:

Mammalian target of rapamycin

NP-40:

Nonidet P-40

PAGE:

Polyacrylamide gels

PBS:

Phosphate buffered saline

PI3K:

Phosphatidylinositol 3-kinase

PKA:

Protein kinase A

PKB:

Protein kinase B

PKC:

Protein kinase C

p70S6k:

p70S6 Kinase

PVDF:

Polyvinylidene difluoride

rT3:

3,3′,5′-Trioiodothyronine

SEM:

Standard error of mean

T3:

3,5,3′-Triiodo-l-thyronine

TBST:

Tris-buffered saline containing Tween 20

TRβ:

Thyroid receptor β

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Acknowledgements

This work was supported by grants to B. M. Li from the Ministry of Science and Technology of China (2006CB500807), the Ministry of Education of China (Program for Changjiang Scholars and Innovative Research Team in University), and the National Natural Science Foundation of China (30225023, 30430240, 30611120530), and supported by the National Natural Science Foundation of China (30670673) to L. Sui. The technical assistance of H. Y. Shan and K. J. Xu is gratefully acknowledged.

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Sui, L., Wang, J. & Li, BM. Administration of Triiodo-l-thyronine into Dorsal Hippocampus Alters Phosphorylation of Akt, Mammalian Target of Rapamycin, p70S6 Kinase and 4E-BP1 in Rats. Neurochem Res 33, 1065–1076 (2008). https://doi.org/10.1007/s11064-007-9551-2

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