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
References
Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81:1097–1142
Dratman MB, Gordon JT (1996) Thyroid hormones as neurotransmitters. Thyroid 6:639–647
Sui L, Gilbert ME (2003) Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144:4195–4203
Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH (2006) Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148:92–102
Sui L, Wang F, Liu F, Wang J, Li BM (2006) Dorsal hippocampal administration of triiodothyronine enhances long-term memory for trace cued and delay contextual fear conditioning in rats. J Neuroendocrinol 18:811–819
Farwell AP, Dubord-Tomasetti SA, Pietrzykowski AZ, Leonard JL (2006) Dynamic nongenomic actions of thyroid hormone in the developing rat brain. Endocrinology 147:2567–2574
D’Arezzo S, Incerpi S, Davis FB, Acconcia F, Marino M, Farias RN, Davis PJ (2004) Rapid nongenomic effects of 3,5,3′-triiodo-l-thyronine on the intracellular pH of L-6 myoblasts are mediated by intracellular calcium mobilization and kinase pathways. Endocrinology 145:5694–5703
Davis PJ, Tillmann HC, Davis FB, Wehling M (2002) Comparison of the mechanisms of nongenomic actions of thyroid hormone and steroid hormones. J Endocrinol Invest 25:377–388
Davis PJ, Davis FB (2002) Nongenomic actions of thyroid hormone on the heart. Thyroid 12:459–466
Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, Davis PJ (2005) Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146:2864–2871
Sui L, Anderson WL, Gilbert ME (2005) Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci 85:647–656
Coffer PJ, Jin J, Woodgett JR (1998) Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 335(Pt 1):1–13
Franke TF, Kaplan DR, Cantley LC (1997) PI3K: downstream AKT ion blocks apoptosis. Cell 88:435–437
Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346(Pt 3):561–576
Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, Nawa H (2004) Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 24:9760–9769
Pullen N, Thomas G (1997) The modular phosphorylation and activation of p70s6k. FEBS Lett 410:78–82
Sonenberg N, Gingras AC (1998) The mRNA 5′ cap-binding protein eIF4E and control of cell growth. Curr Opin Cell Biol 10:268–275
Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G (1997) Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J 16:3693–3704
Pause A, Methot N, Svitkin Y, Merrick WC, Sonenberg N (1994) Dominant negative mutants of mammalian translation initiation factor eIF-4A define a critical role for eIF-4F in cap-dependent and cap-independent initiation of translation. EMBO J 13:1205–1215
Lawrence JCJ, Abraham RT (1997) PHAS/4E-BPs as regulators of mRNA translation and cell proliferation. Trends Biochem Sci 22:345–349
Cao X, Kambe F, Moeller LC, Refetoff S, Seo H (2005) Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts. Mol Endocrinol 19:102–112
Hiroi Y, Kim HH, Ying H, Furuya F, Huang Z, Simoncini T, Noma K, Ueki K, Nguyen NH, Scanlan TS, Moskowitz MA, Cheng SY, Liao JK (2006) Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci USA 103:14104–14109
Kuzman JA, Vogelsang KA, Thomas TA, Gerdes AM (2005) l-thyroxine activates Akt signaling in the heart. J Mol Cell Cardiol 39:251–258
Kuzman JA, Gerdes AM, Kobayashi S, Liang Q (2005) Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. J Mol Cell Cardiol 39:841–844
Lei J, Mariash CN, Ingbar DH (2004) 3,3′,5-Triiodo-l-thyronine up-regulation of Na,K-ATPase activity and cell surface expression in alveolar epithelial cells is Src kinase- and phosphoinositide 3-kinase-dependent. J Biol Chem 279:47589–47600
Storey NM, O’Bryan JP, Armstrong DL (2002) Rac and Rho mediate opposing hormonal regulation of the ether-a-go-go-related potassium channel. Curr Biol 12:27–33
Storey NM, Gentile S, Ullah H, Russo A, Muessel M, Erxleben C, Armstrong DL (2006) Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone. Proc Natl Acad Sci USA 103:5197–5201
Furuya F, Hanover JA, Cheng SY (2006) Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor. Proc Natl Acad Sci USA 103:1780–1785
Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ (2001) Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 22:451–476
Rong Y, Baudry M (1996) Seizure activity results in a rapid induction of nuclear factor-kappa B in adult but not juvenile rat limbic structures. J Neurochem 67:662–668
Borgatti P, Martelli AM, Bellacosa A, Casto R, Massari L, Capitani S, Neri LM (2000) Translocation of Akt/PKB to the nucleus of osteoblast-like MC3T3-E1 cells exposed to proliferative growth factors. FEBS Lett 477:27–32
Pekarsky Y, Koval A, Hallas C, Bichi R, Tresini M, Malstrom S, Russo G, Tsichlis P, Croce CM (2000) Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Proc Natl Acad Sci USA 97:3028–3033
Schapira M, Raaka BM, Das S, Fan L, Totrov M, Zhou Z, Wilson SR, Abagyan R, Samuels HH (2003) Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking. Proc Natl Acad Sci USA 100:7354–7359
Raught B, Gingras AC, Sonenberg N (2001) The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA 98:7037–7044
Kim JE, Chen J (2000) Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Proc Natl Acad Sci USA 97:14340–14345
Lubin FD, Johnston LD, Sweatt JD, Anderson AE (2005) Kainate mediates nuclear factor-kappa B activation in hippocampus via phosphatidylinositol-3 kinase and extracellular signal-regulated protein kinase. Neuroscience 133:969–981
Davis PJ, Davis FB, Cody V (2005) Membrane receptors mediating thyroid hormone action. Trends Endocrinol Metab 16:429–435
Shohet RV, Kisanuki YY, Zhao XS, Siddiquee Z, Franco F, Yanagisawa M (2004) Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy. Proc Natl Acad Sci USA 101:2088–2093
Kenessey A, Ojamaa K (2006) Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. J Biol Chem 281:20666–20672
Neri LM, Borgatti P, Capitani S, Martelli AM (2002) The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system. Biochim Biophys Acta 1584:73–80
Irvine RF (2003) 20 Years of Ins(1,4,5)P3, and 40 years before. Nat Rev Mol Cell Biol 4:586–590
de Groot RP, Ballou LM, Sassone-Corsi P (1994) Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression. Cell 79:81–91
Minami T, Hara K, Oshiro N, Ueoku S, Yoshino K, Tokunaga C, Shirai Y, Saito N, Gout I, Yonezawa K (2001) Distinct regulatory mechanism for p70 S6 kinase beta from that for p70 S6 kinase alpha. Genes Cells 6:1003–1015
Kikani CK, Dong LQ, Liu F (2005) “New”-clear functions of PDK1: beyond a master kinase in the cytosol? J Cell Biochem 96:1157–1162
Kim SJ, Kahn CR (1997) Insulin stimulates p70 S6 kinase in the nucleus of cells. Biochem Biophys Res Commun 234:681–685
Ye K (2005) PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death. J Cell Biochem 96:463–472
Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, Francesconi W (2002) Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J Neurosci 22:3359–3365
Tang SJ, Reis G, Kang H, Gingras AC, Sonenberg N, Schuman EM (2002) A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc Natl Acad Sci USA 99:467–472
Cammalleri M, Lutjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP (2003) Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proc Natl Acad Sci USA 100:14368–14373
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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DOI: https://doi.org/10.1007/s11064-007-9551-2