Nongenomic Influences of Thyroid Hormones and Their Metabolites in Adults: A Tribute to Mary B. Dratman

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Background

Early studies suggested that in adulthood the general metabolism of the adult brain is not influenced by thyroid hormones, and, for many years, the adult CNS was considered to be a “thyroid-insensitive tissue”. In contrast, during development of the brain the mechanisms are generally “genomic”, relying on the nuclear mechanisms regulating gene expression.

However, hypothyroidism in adults is characterized by somnolence, progressive intellectual deterioration, hypothermia, bradycardia and, in extreme cases, coma. In contrast, manifestations of hyperthyroidism include nervousness, physical hyperactivity, emotional lability, anxiety, tachycardia, hyperthermia and, in the most extreme instances, seizures. While these presumably brain actions can be life-threatening, the mechanisms of actions of thyroid hormones in the adult brain are rapidly being clarified.

This special issue of the Thyroid Section of Frontiers in Endocrinology is a tribute to Dr. Mary B. Dratman, a seminal researcher in the field, who passed away recently at 101 years of age. The work of Dr. Dratman showed that injections of radiolabeled L triiodothyronine tend to concentrate label in nerve terminals (by autoradiography) or in nerve-terminal fractions (synaptosomes) from adult rat brain. This finding implies that the molecules would have signaling roles. In earlier publications, she also noted that thyroid hormones are aromatic amino acids and, like all other such amino acids, should be sensitive to decarboxylation to amines. In the case of thyroid hormones (thyronines), the resulting molecules are thyronamines, which are present in brain, and have numerous physiological effects. Dratman (and others) advanced the hypothesis that thyroid hormones or their derivatives act as neurotransmitters, particularly in the CNS.

The goals and scope of the current proposal are to examine the potential roles of thyroid hormones and their derivatives as neurotransmitters. The definition of a neurotransmitter includes several measurable characteristics. To be a neurotransmitter a substance should show:

1) Presence in the tissue - thyroid hormones and their derivatives selectively accumulate in brain regions and particular tissues. Thyronamines selectively increase in brain and other tissues over blood.

2) Release from tissue or cell - this research area is not yet well-developed.

3) Binding to a high-affinity and saturable recognition site - iodothyronines bind to GABA-A, nicotinic, muscarinic, glutamatergic, and catecholamine receptors, usually at allosteric modulatory sites. Thyronines have a direct effect on a specific membrane receptor. Thyronamines bind directly to the active site of TAAR1 receptors.

4) Inactivation - the decarboxylated thyronines (thyronamines) are sensitive to monoamine oxidase (MAO) with 3-iodothyronamine (T1AM) converted into 3-iodothyroacetic acid (TA1). Brain-specific deiodinases also have a role in inactivating thyronines and thyronamines.

5) Triggering of a specific effector mechanism - thyronines alter the activity of the Na+/K+ ATPase, decrease GABA-stimulated Cl- flux and currents, and stimulate nongenomic protein synthesis in a nucleus-free brain preparation. Thyronines activate G-proteins. Both thyronines and thyronamines have complex inhibitory effects on sleep and thermoregulation. Effects of thyroid hormone on thermoregulation persist following elimination of genomic effects.

The current proposal seeks manuscripts of original research or reviews of the relevant literature on nongenomic effects of thyroid hormones or their metabolites in adult tissues, especially CNS.

Keywords: thyroid hormones, neurotransmitters, Thyronines, thyronamines, nongenomic protein synthesis, CNS

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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