Thyroid Hormone Transporters — Functions and Clinical Implications

Thyroid Hormone Transporters

Thyroid hormones regulate many metabolic and developmental processes, including key having functions in the brain, and mutations in a transporter specific for thyroid hormone leads to severe neurological impairment. This review article attempts to discuss the physiological importance and clinical implications of thyroid hormone transport, with a particular focus on brain development.

The thyroid hormones, T4 (3,5,3′,5′tetraiodo-L-thyronine) and T3 (3,5,3′tri-iodo-L-thyronine; also known as tri-iodothyronine) are iodinated amino acids produced and secreted by the thyroid gland. These hormones regulate many developmental and metabolic processes. The nuclear T3 receptors are ligand-modulated transcription factors encoded by two genes, THRA and THRB. These genes encode several receptor proteins, of which three (thyroid hormone receptor α1, thyroid hormone receptor β1 and thyroid hormone receptor β2) interact with T3, which results in tissue-specific and developmentally-dependent transcriptomic changes. In the developing cerebral cortex, 500–1,000 genes are directly or indirectly affected by thyroid hormones. In addition, both T4 and T3 perform nongenomic, extranuclear actions. For example, T3 might interact with a plasma-membrane-associated thyroid hormone receptor α variant, and with cytoplasmic thyroid hormone receptor β, while T4 interacts with integrin αvβ3 and activates diverse signalling pathways such as the phosphoinositide 3-kinase pathway and mitogen-activated protein kinase pathways.

Metabolism of thyroid hormones includes the processes of deiodination, deamination, decarboxylation, sulphation and glucuronidation, which have been extensively reviewed elsewhere. The most relevant pathway for the discussion in this Review is deiodination, a process that activates or inactivates thyroid hormones. Deiodinases are selenoproteins that catalyze the removal of specific iodine atoms from the phenolic or tyrosyl rings of the iodothyronine molecule. Type 1 iodothyronine deiodinase and type 2 iodothyronine deiodinase (DIO1 and DIO2, encoded by the DIO1 and DIO2 genes, respectively) have phenolic, or 'outer' ring, activity and convert T4 to T3. In extrathyroidal tissues, this pathway generates ∼80% of the total body pool of T3. Type 3 iodothyronine deiodinase (DIO3, encoded by the DIO3 gene) and DIO1 have tyrosyl, or 'inner' ring, activity and convert T4 and T3 to the inactive metabolites 3,3′5′-triiodo-L-thyronine (rT3) and 3,3′-diiodo-L-thyronine (T2), respectively; rT3 is then further metabolized by DIO1 to T2.

• Many proteins can mediate thyroid hormone transport, but only mutations in genes encoding MCT8, MCT10 and OATP1C1 have pathophysiological effects attributed to this process

• MCT8 mutations lead to Allan–Herndon–Dudley syndrome, which is characterized by truncal hypotonia and results in spastic quadriplegia, lack of speech, severe intellectual deficit and altered thyroid hormone concentrations

• MCT8 deficiency impairs the transfer of thyroid hormones across the blood–brain barrier

• Mct8-deficient mice lack neurological impairment possibly due to the presence of Oatp1c1, a T4 transporter, but levels of OATP1C1 in the primate blood–brain barrier are very low

• Histopathological studies of patients with mutations in MCT8 support the concept that defective thyroid hormone action in the brain during development leads to the neurological syndrome

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CLIA and regulatory readiness: How can your lab always be ready?

Much has been written about laboratory regulations and the regulatory process. Why publish another article now? Changes to the healthcare environment in the United States over the past few years have left hospitals and laboratories asking questions about resources. How does the laboratory continue to provide quality service to patients and practitioners while reimbursements decrease? How do regulatory requirements fit into this same picture? How can the laboratory stay ahead of new regulations?

Many laboratories do maintain readiness throughout the inspection cycle. These facilities share common traits. This article will identify success strategies when dealing with regulatory compliance. In general, these strategies fall into three categories: 1) knowledge, 2) awareness, and 3) good management practices.

Read more: CLIA and regulatory readiness: How can your lab always be ready?

Source: aapc

Brain signalling regulation by nerve terminal nanofilaments

State-of-the-art electron microscopy reveals the large-scale organization of the proteins that regulate neurotransmitter release

This spectacular image – which took the best part of a year to create – shows the fine structure of a nerve terminal at high resolution, revealing, for the very first time, an intricate network of fine filaments that controls the movements of synaptic vesicles.

The brain is soft and wet, with the consistency of a lump of jelly. Yet, it is the most complex and highly organized structure that we know of, containing hundreds of billions of neurons and glial cells, and something on the order of one quadrillion synaptic connections, all of which are arranged in a very specific manner.

This high degree of specificity extends down to the deepest levels of brain organization. Just beneath the membrane at the nerve terminal, synaptic vesicles store neurotransmitter molecules, and await the arrival of a nervous impulse, whereupon they fuse with the membrane and release their contents into the synaptic cleft, the miniscule gap at the junction between nerve cells, and diffuse across it to bind to receptor protein molecules embedded at the surface of the partner cell.

Read more: Brain signalling regulation by nerve terminal nanofilaments

3D reconstruction showing three types of nanofilaments that connect to synaptic
vesicles in the nerve terminals of excitatory synapses in the rat hippocampus.

Source: Cole, A. A., et al., Journal of Neuroscience (2016)