What is the mechanism of action of thyroid hormones at a cellular level? Describe the effects of thyroid hormones on each of the following:

(a) heart rate and contractility

(b) the development and function of the nervous system

(c) metabolic rate and heat production

Essay:

            Thyroid hormone (T₃ and T₄) enter cells by a carrier-mediated, energy-dependent process. Thyroid hormone binds to a nuclear receptor protein of the steroid hormone-vitamin D family. The thyroid receptor (TR) is usually found bound to thyroid regulatory elements (TREs) in target genes. The receptor’s DNA binding domain consists of 2 zinc fingers. A zinc finger is a motif of a protein consisting of a loop with a zinc atom complexed by 4 cysteine residues. One zinc finger binds DNA in a sequence-specific manner while the other zinc finger is responsible for dimerization. TR constitutively represses most gene expression. Binding of thyroid hormone to TR relieves the repression exerted through the TRE, and thus gene expression is induced.

            TREs have two half-sites with the nucleotide base sequence AGGTCA. Two TRs can form a homodimer that binds to both TRE half-sites, but more often one TR molecule and one retinoid receptor molecule form heterodimer that, when bound to thyroid hormone, activates the target gene. The two TRE half-sites can function as direct repeats of each other, palindromes.

(a)        Thyroid hormone increases cardiac output, ensuring sufficient oxygen delivery to the tissues. The resting heart rate and stroke volume are both increased. The speed and force of myocardial contractions are enhanced. The cardiac inotropic effects are partly indirect, via adrenergic stimulation and partly direct. Myocardial calcium uptake and adenylyl cyclase activity are increased and enhance contractile force. Thyroid hormone induces the myosin heavy-chain alpha gene and represses the beta gene, thereby increasing the velocity of myocardial contraction. The calcium-ATPase of the sarcolemmal reticulum is increased, which facilitates sequestration of calcium during diastole and shortens the relaxation time.

(b)        Thyroid hormone is performs a critical set of actions on the timing and pace of development of the central nervous system. It is essential for the growth of the cerebral and cerebellar cortex, proliferation of axons, branching of dendrites, synaptogenesis, myelinization and cell migration. The crucial role of thyroid hormone in central nervous system development is underscored by the fact that brain-specific thyroid receptors are increased in the cortex of the brain of neonatals.

            Thyroid hormone affects the functioning of the central nervous system. It enhances wakefulness, alertness, responsiveness to various stimuli, auditory sense, awareness of hunger, memory and learning capacity. Normal emotional tone also depends on proper thyroid hormone availability. Furthermore, the speed and amplitude of peripheral nerve reflexes are increased by thyroid hormone.

(c)        Thyroid hormone increases the metabolic rate of almost all metabolically active tissues except the brain, spleen and gonads. Thyroid hormone increase the activity of the membrane-bound Na⁺-K⁺-ATPase in many tissues and it is thought that it is the increase in energy consumption associated with the increase in Na⁺ transport which is responsible for the increase in metabolic rate though evidence for this theory is flimsy. Thermogenesis also increase with oxygen use. The potential increase in body temperature, however, is moderated by a compensatory increase in heat loss through appropriate thyroid hormone-mediated increases in blood flow, sweating and ventilation.