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  • Review Article
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Nongenomic actions of thyroid hormone

Nature Reviews Endocrinology volume 12, pages 111–121 (2016)Cite this article

Subjects

Key Points

  • The nongenomic actions of thyroid hormone include the modulation of angiogenesis and stimulation of proliferation of tumour cells and osteocytes; cytoskeletal microfilaments and mitochondrial respiration can also be nongenomically regulated

  • Nongenomic actions are initiated at receptors other than the intranuclear thyroid hormone receptors that mediate genomic effects initiated by T3

  • These receptors might be structurally related to nuclear thyroid hormone receptors, such as truncated TRα isoforms in mitochondria, in the cytoplasm or at the plasma membrane

  • The receptors can also be structurally unrelated to thyroid hormone receptors, for example, the receptor on plasma membrane integrin αvβ3

  • T4 itself might initiate nongenomic functions mediated by integrin αvβ3

  • The nongenomic and genomic actions of thyroid hormone can overlap, for example, T4 regulates intracellular trafficking of proteins, including hormone receptors, and consequently the phosphorylation of intranuclear thyroid hormone receptors

Abstract

The nongenomic actions of thyroid hormone begin at receptors in the plasma membrane, mitochondria or cytoplasm. These receptors can share structural homologies with nuclear thyroid hormone receptors (TRs) that mediate transcriptional actions of T3, or have no homologies with TR, such as the plasma membrane receptor on integrin αvβ3. Nongenomic actions initiated at the plasma membrane by T4 via integrin αvβ3 can induce gene expression that affects angiogenesis and cell proliferation, therefore, both nongenomic and genomic effects can overlap in the nucleus. In the cytoplasm, a truncated TRα isoform mediates T4-dependent regulation of intracellular microfilament organization, contributing to cell and tissue structure. p30 TRα1 is another shortened TR isoform found at the plasma membrane that binds T3 and mediates nongenomic hormonal effects in bone cells. T3 and 3,5-diiodo-L-thyronine are important to the complex nongenomic regulation of cellular respiration in mitochondria. Thus, nongenomic actions expand the repertoire of cellular events controlled by thyroid hormone and can modulate TR-dependent nuclear events. Here, we review the experimental approaches required to define nongenomic actions of the hormone, enumerate the known nongenomic effects of the hormone and their molecular basis, and discuss the possible physiological or pathophysiological consequences of these actions.

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Figure 1: The nongenomic actions of thyroid hormone.
Figure 2: T4 interactions with human TRΔα1 ligand binding domain.
Figure 3: Mechanisms of direct actions of iodothyronines T3 and T2 on mitochondria.

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Acknowledgements

K. A. Keating (Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, New York, USA) provided invaluable editorial assistance to the preparation of the manuscript.

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Authors and Affiliations

  1. Pharmaceutical Research Institute, Albany College of Pharmacy & Health Sciences, One Discovery Drive, Rennselaer, 12144, New York, USA

    Paul J. Davis

  2. Dipartimento di Scienze e Tecnologie, Università degli studi del Sannio, Via Port'Arsa 11, Benevento, 82100, Italy

    Fernando Goglia

  3. Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, 368 Plantation Street, Worcester, 01605, Massachusetts, USA

    Jack L. Leonard

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All authors contributed equally to all aspects of the manuscript.

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Correspondence to Paul J. Davis.

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Competing interests

P.J.D. is co-inventor of a nanoparticulate formulation of tetrac and a minority stockholder in the company that owns the patent. F.G. and J.L.L. declare no competing interests.

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Davis, P., Goglia, F. & Leonard, J. Nongenomic actions of thyroid hormone. Nat Rev Endocrinol 12, 111–121 (2016). https://doi.org/10.1038/nrendo.2015.205

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