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Author Spotlight: In Vivo Assessment of Thyroid Hormone Disruption Using the THAI Mouse Model
Published on: October 6, 2023
Extranuclear effects of thyroid hormones and analogs during development: An old mechanism with emerging roles
Sandra Incerpi1, Fabio Gionfra1, Roberto De Luca2
1Department of Sciences, University Roma Tre, Roma, Italy.
Abstract:
Thyroid hormones, T3 (triiodothyronine) and T4 (thyroxine), induce a variety of long-term effects on important physiological functions, ranging from development and growth to metabolism regulation, by interacting with specific nuclear or cytosolic receptors. Extranuclear or nongenomic effects of thyroid hormones are mediated by plasma membrane or cytoplasmic receptors, mainly by αvβ3 integrin, and are independent of protein synthesis. A wide variety of nongenomic effects have now been recognized to be elicited through the binding of thyroid hormones to this receptor, which is mainly involved in angiogenesis, as well as in cell cancer proliferation. Several signal transduction pathways are modulated by thyroid hormone binding to αvβ3 integrin: protein kinase C, protein kinase A, Src, or mitogen-activated kinases. Thyroid hormone-activated nongenomic effects are also involved in the regulation of Na+-dependent transport systems, such as glucose uptake, Na+/K+-ATPase, Na+/H+ exchanger, and amino acid transport System A. Of note, the modulation of these transport systems is cell-type and developmental stage-dependent. In particular, dysregulation of Na+/K+-ATPase activity is involved in several pathological situations, from viral infection to cancer. Therefore, this transport system represents a promising pharmacological tool in these pathologies.
Insights
Thyroid hormones exert rapid, nongenomic effects via cell membrane receptors, influencing key cellular processes like angiogenesis and cancer proliferation. These actions, independent of protein synthesis, highlight novel therapeutic targets.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Biology
Background:
- Thyroid hormones (triiodothyronine [T3] and thyroxine [T4]) regulate physiological functions via nuclear/cytosolic receptors.
- Extranuclear, nongenomic effects of thyroid hormones occur independently of protein synthesis.
- These nongenomic effects are mediated by plasma membrane or cytoplasmic receptors, notably αvβ3 integrin.
Purpose of the Study:
- To explore the nongenomic effects of thyroid hormones mediated by αvβ3 integrin.
- To identify signal transduction pathways and cellular processes influenced by this interaction.
- To investigate the role of thyroid hormone-bound αvβ3 integrin in regulating Na+-dependent transport systems.
Main Methods:
- The study focuses on the molecular mechanisms of thyroid hormone action at the plasma membrane.
- It examines the modulation of signal transduction pathways (PKC, PKA, Src, MAPK) by thyroid hormone-αvβ3 integrin binding.
- It investigates the impact on Na+-dependent transport systems, including glucose uptake and Na+/K+-ATPase.
Main Results:
- Thyroid hormone binding to αvβ3 integrin triggers nongenomic effects, impacting angiogenesis and cancer cell proliferation.
- Several key signal transduction pathways are modulated by this interaction.
- Thyroid hormones regulate Na+-dependent transport systems, with cell-type and developmental stage specificity.
Conclusions:
- Nongenomic thyroid hormone actions via αvβ3 integrin play significant roles in cellular processes beyond traditional genomic effects.
- Modulation of Na+-dependent transport systems, particularly Na+/K+-ATPase, by thyroid hormones has implications in various pathologies.
- The Na+/K+-ATPase system presents a potential pharmacological target for diseases involving its dysregulation.
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