Minireview: thyroid hormone transporters: the knowns and the unknowns

Abstract

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

Fig. 1.

Model of TH regulation in brain. Transporters (paired ovals) are required for uptake and release of T₄ and T₃. D2 converts T₄ to bioactive T₃, whereas D3 degrades T₃ to 3,3′-T₂. T₃ in brain is either derived from the circulation [via the blood-brain barrier or indirectly via the blood-cerebrospinal fluid (CSF) barrier] or locally produced from T₄ in astrocytes by D2. Intracellular T₃-binding proteins (e.g. CRYM) may store cytoplasmic T₃ and function in intracellular T₃ transport. Ultimately, T₃ binds to its nuclear receptor (TR) and modulates gene expression of T₃-target genes. T₃ actions in mitochondria also require transporter proteins. All principal cells of the brain are T₃ targets: neurons, astrocytes, and oligodendrocytes. The degree of certainty of this model is reflected by the color of the symbols. Filled symbols reflect established knowledge (the knowns). White symbols are surmised concepts (the unknowns). Question marks indicate possible novel players or functions in local TH regulation (the guesses). RXR, Retinoic X receptor; TRE, T₃-responsive element.

Fig. 2.

Thyroid parameters in serum from 17 families with MCT8 mutations. Serum levels (mean ± SE) of (A) TSH, (B) fT₄, (C) T₃, and (D) rT₃ in affected males (Pat, squares), unaffected heterozygous females (Het, triangles), and unaffected family members (Nor, circles).