Reverse T3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms. (15th July 2018)

• Record Type: Journal Article
• Authors: Domingues, Juliana Tonietto; Cattani, Daiane; Cesconetto, Patricia Acordi; Nascimento de Almeida, Bianka Alzira; Pierozan, Paula; dos Santos, Karin; Razzera, Guilherme; Mena Barreto Silva, Fátima Regina; Pessoa-Pureur, Regina; Zamoner, Ariane
• Is Part Of: Molecular and cellular endocrinology. Volume 470(2018)
• Page Start: 281
• Page End: 294
• Publication Date: 2018-07-15
• Subjects: 3, 3′, 5′-triiodothyronine (reverse T3, rT3) -- Thyroid hormone -- Nongenomic effects -- Modeling -- glutamate -- Integrin; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2017.11.013
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: In the present study we provide evidence that 3, 3′, 5′-triiodothyronine (reverse T3, rT3 ) restores neurochemical parameters induced by congenital hypothyroidism in rat hippocampus. Congenital hypothyroidism was induced by adding 0.05% propylthiouracil in the drinking water from gestation day 8 and continually up to lactation day 15. In the in vivo rT3 exposure, hypothyroid 12-day old pups were daily injected with rT3 (50 ng/kg body weight) or saline until day 14. In the ex vivo rT3 treatment, hippocampal slices from 15-day-old hypothyroid pups were incubated for 30 min with or without rT3 (1 nM). We found that ex vivo and/or in vivo exposure to rT3 failed in restoring the decreased 14 C-glutamate uptake; however, restored the phosphorylation of glial fibrillary acidic protein (GFAP), 45 Ca 2+ influx, aspartate transaminase (AST), glutamine synthetase (GS) and gamma-glutamate transferase (GGT) activities, as well as glutathione (GSH) levels in hypothyroid hippocampus. In addition, rT3 improved 14 C-2-deoxy-D-glucose uptake and lactate dehydrogenase (LDH) activity. Receptor agonists/antagonists (RGD peptide and AP-5), kinase inhibitors of p38MAPK, ERK1/2, CaMKII, PKA (SB239063, PD98059, KN93 and H89, respectively), L-type voltage-dependent calcium channel blocker (nifedipine) and intracellular calcium chelator (BAPTA-AM) were used to determine the mechanisms of the nongenomic rT3 action on GGT activity. Using molecular docking analysis, we found rT3 interaction with αvβ3 integrin receptors, nongenomically activating signaling pathways (PKA, CaMKII, p38MAPK) that restored GGT activity. We provide evidence that rT3 is an active TH metabolite and our results represent an important contribution to elucidate the nonclassical mechanism of action of this metabolite in hypothyroidism. Graphical abstract: Highlights: Reverse T3 interacts with αvβ3 integrin receptor. rT3 restores hypothyroid-induced Ca 2+ accumulation. Nongenomic action of rT3 restores the hypothyroid-induced oxidative stress. rT3 improves energy metabolism in hypothyroid hippocampus. rT3 action depends on p38, CaMKII and PKA cell signaling pathways.