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[Mechanism of action of thyroid hormones at the cellular level]
Abstract:
Thyroid hormones exert pleiotropic effects at the cell level and several theories to define the initial site of action have been proposed. First mitochondria, nuclei or plasma membrane were considered as the main regulatory step. More recently, evidence of T3 and/or T4 binding sites present in different cellular compartments suggests the existence of more than one initial site of action. Binding sites from cytosol or plasma membrane and endoplasmic reticulum seem to participate either in the storage of thyroid hormones, or in their intracellular transport and metabolism. Mitochondrial and certain plasma membrane binding sites could be responsible for rapid effects of thyroid hormones at their level. Nuclear T3 binding sites located in the chromatin are considered as a true hormone receptor and are more documented in a structural and functional point of view. They may mediate thyroid hormone effects on the regulation of DNA transcription and the synthesis of active proteins. Their mechanism of action is nevertheless not well defined.
Insights
Thyroid hormones act on multiple cellular sites, including mitochondria, plasma membranes, and nuclei. These locations suggest diverse mechanisms for thyroid hormone action beyond nuclear receptors.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Biology
Context:
- Thyroid hormones (TH), including thyroxine (T4) and triiodothyronine (T3), are crucial regulators of cellular metabolism and development.
- Historically, the primary site of TH action was believed to be nuclear, mediating transcriptional regulation.
- Emerging evidence points to extranuclear actions, necessitating a re-evaluation of TH signaling pathways.
Purpose:
- To explore the diverse cellular locations and potential functions of thyroid hormone binding sites.
- To synthesize current understanding of both nuclear and extranuclear actions of thyroid hormones.
- To highlight the complexity of thyroid hormone signaling and identify areas requiring further investigation.
Summary:
- Thyroid hormones (T3 and T4) bind to sites in various cellular compartments, including mitochondria, plasma membrane, cytosol, endoplasmic reticulum, and nucleus.
- Extranuclear binding sites may be involved in hormone storage, transport, metabolism, and rapid cellular responses.
- Nuclear binding sites in chromatin are well-characterized receptors mediating gene transcription, though their precise mechanism remains under investigation.
Impact:
- This review broadens the understanding of thyroid hormone signaling, moving beyond the classical nuclear receptor model.
- It emphasizes the potential for rapid, non-genomic effects of thyroid hormones mediated by extranuclear targets.
- Further research into these extranuclear actions could reveal novel therapeutic targets for endocrine disorders.