Thethyroid hormone receptor (TR)^[1] is a type ofnuclear receptor that is activated by bindingthyroid hormone.^[2] TRs act astranscription factors, ultimately affecting the regulation of genetranscription andtranslation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.^[3]

There are fourdomains that are present in all TRs.^[4] Two of these, theDNA-binding (DBD) and hinge domains, are involved in the ability of the receptor to bindhormone response elements (HREs). TRs also have a ligand binding domain (LBD) that allows them to bind tothyroid hormone with high affinity. The fourth domain is atransactivation domain which allows the receptor to bind othertranscription factors.

Thyroid hormone receptors play critical roles in the regulation ofmetabolism,heart rate, anddevelopment of organisms.^[5][6][7]

These receptors are typically associated with retinoic acid receptors (RXR), forming heterodimers. In its inactivated form, the TR inhibits gene transcription by binding corepressors. This adds an additional level of regulation to an already tightly regulated process. When activated, these receptors become associated with other activators and initiate gene transcription. TRs are also involved in cell viability, and are believed to have other non-genomic affects that are currently being investigated.^[3]

Thyroid hormone is transported into the cell through a transporter. Once inside of the cell, the hormone can have genomic or non-genomic effects.^[3] The genomic signaling pathway directly influences genetranscription andtranslation, while the non-genomic pathway involves more rapid, cellular changes, some of which also regulate gene expression through more indirect signaling.^[8]

Thyroid hormone receptorsregulate gene expression by binding tohormone response elements (HREs) in DNA either asmonomers,heterodimers with other nuclear receptors, orhomodimers.^[4] Dimerizing with different nuclear receptors leads to the regulation of different genes. THR commonly interacts with theretinoid X receptor (RXR), a nuclear retinoic acid receptor.^[9] TR/RXR heterodimers are the most transcriptionally active form of TR.^[10]

Retinoic acid receptors are located in the nucleus and commonly form complexes with steroid hormone receptors in order to regulate the production of essential gene products.^[9] Retinoic acid receptors bindcorepressors in the absence of their ligand,retinoic acid, which is formed from the metabolism ofvitamin A. Retinoid X receptors are activated by binding to9-cis-retinoic acid, a specific isomer of retinoic acid. Other retinoic acid receptors are less specific, allowing them to bind isomers of retinoic acid with similar affinities.

Once RXRs bind ligand, they undergo conformational changes that reduce their affinity for corepressors—allowing them to attractcoactivators to the transcription site. Once all of the necessarycofactors are present, the presence of a DNA binding domain permits the binding of response elements, initiating gene transcription. Due to their role in gene regulation, studies have shown that these receptors are necessary for growth and development.

In the absence of hormone, TR forms a complex withcorepressor proteins such asnuclear receptor co-repressor 1 (N-CoR) and2 (N-CoR2).^[4] While these cofactors are present, TR binds HREs in a transcriptionally inactive state.^[3] This inhibition of genetranscription allows for tight regulation of gene products. Binding of thyroid hormone results in a conformational change in helix 12 of the TRtransactivation domain, which displaces the corepressors from the receptor/DNA complex.^[4]Coactivator proteins are recruited, forming a DNA/TR/coactivator complex. One coactivator recruited to the site isnuclear receptor co-activator 1 (NCoA-1).RNA polymerase is recruited to the site and transcribes downstream DNA intomessenger RNA (mRNA). The mRNA generated is thentranslated into the corresponding proteins. The protein products from this process drive the changes in cell function observed in the presence of thyroid hormone.

Non-genomic effects are faster than genomic effects because they do not require transcription and translation—two very precise and time-consuming processes.^[11] Initially most scientists presumed that non-genomic effects were mediated by non-nuclear receptors, but now there is growing evidence for non-genomic effects mediated in the cytoplasm by the traditional nuclear receptors.^[12] For example, TR-α1 (a specificisoform of TR) has been linked to cell viability,^[3] which is hypothesized to involve a rise in cGMP concentration (through an unknown mechanism) and the corresponding activation ofprotein kinase G.^{[citation needed]}

Other non-genomic effects that have been observed include the regulation of mitochondrialmetabolism, stimulation ofglucose uptake, altering cytoskeleton organization, regulating ion pump concentrations at the membrane, and the regulation of osteogenesis.^[11] Unfortunately, no specific molecular mechanisms have been provided for these nongenomic signaling pathways, so testing the relative importance of genomic and nongenomic signaling by the nuclear receptors using specific mutations that selectively eliminate one action or the other was not carried out. In contrast, more recently, a specific molecular mechanism forTR-β signaling through the PI3 kinase has been identified,^[13] which allowed scientists to obtain direct genetic evidence for the involvement ofTR-β signaling through the PI3 kinase in brain development^[13] and metabolism,^[14] two of the primary physiological effects of thyroid hormone action.

There are two main classes of thethyroid hormone receptor:alpha andbeta.^[3] The localization of these subtypes, summarized inTable 1, is largely dependent upon post-transcriptionalsplicing. Genes on chromosomes 3 and 17 are transcribed and translated into c-erbAgene products. Splicing of these gene products leads to the production of differentisoforms. There are threeTR-α receptor splice variants encoded by theTHRA (thyroid hormone receptor alpha) gene and threeTR-β isoform splice variants encoded by theTHRB (thyroid hormone receptor beta) gene.^[4] Of these variants, thyroxine is only able to bind to four of them: TR-α1, TR-β1, TR-β2, and TR-β3.^[4]

Certainmutations in the thyroid hormone receptor are associated withthyroid hormone resistance.^[15] The clinical diagnosis ofthyroid hormone resistance syndrome (THRS) depends on the location of the resistance, which can be localized to the pituitary gland, peripheral tissues, or both.^[16] Patients who present with resistance in both tissue types are diagnosed with global resistance to thyroid hormone. Mutations to both TR genes have been observed clinically, however, THRB gene mutations are much more common.

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TR-β resistance is anautosomal dominant disease.^[4] This means only one copy of the mutated gene onchromosome 3 needs to be inherited in order for an individual to present with this condition.THRB mutation directly affects the regulation of thehypothalamic-pituitary-thyroid (HPT) axis. In a healthy individual, the TR-β2 expressed in the pituitary gland plays a major role in regulatingthyroid-stimulating hormone (TSH) levels throughnegative feedback. TSH stimulates the thyroid to secrete thyroid hormone. Once secreted, thyroid hormone acts on these receptors and inhibits transcription ofTshb. This feedback inhibition stops further TSH production, inhibiting thyroid hormone secretion downstream. When the THRB gene is mutated, the receptors on the pituitary can no longer bind thyroid hormone. Due to this, TSH production and secretion is not regulated to the same degree and the thyroid continues to be stimulated. The elimination of thenegative feedback loop results in the heightened levels of thyroid hormone presented by patients with this condition.

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TheTHRA gene is located onchromosome 17.^[4] Not as much information is known about mutations to this gene because it is far less common than mutations toTHRB.^{[citation needed]} Unlike THRB mutations,THRA mutations do not disrupt the HPT axis. This can makeTR-α resistance more difficult to diagnose because patients do not typically present with elevations in thyroid hormone concentration. Due to the high TR-α1 expression in the heart, the cardiovascular system is highly affected by this condition. Additionally, thyroid hormone plays an important role in bone development. Thus, patients with this condition have consistently presented with short stature.

Symptoms of thyroid hormone resistance syndrome can be similar to those seen inhypothyroidism.^[4]Hypothyroidism is a disease in which thethyroid does not produce enoughthyroid hormone. Patients with this condition have also presented with symptoms similar tohyperthyroidism. In contrast tohypothyroidism,hyperthyroidism is a disease in which the thyroid produces too much thyroid hormone. Due to the large array of potential symptoms, this condition can be misleading and is often difficult for medical professionals to diagnose.

Common symptoms of TR mutation include:

• Depression
• Loss of vision
• Heart problems
• Weight gain
• Fatigue
• Hearing loss
• Sensitivity to cold
• Weakness
• Issues withdigestion
• Cognitive impairment
• Changes to themenstrual cycle

Treating patients withhypothyroidism caused by the absence of functional TRs is difficult.^[16] Treatments prescribed to patients withthyroid hormone resistance largely depend on the symptoms they present and the type of resistance they have.

For those whose conditions mimic hypothyroidism, prescribing normal thyroid hormone doses may not remedy the symptoms they are experiencing. In order for a ligand to have an effect, it must be able to bind to a receptor. Individuals with aTHRB orTHRA mutation have less receptors that are able to bind ligand, and a corresponding drop in tissue responsiveness to thyroid hormone. For this reason, physicians may prescribe higher doses of the hormone to increase the probability that the ligand will reach a TR that is functional.

Prescribing thyroid hormone in any dose to patients presenting with symptoms mimickinghyperthyroidism does not improve the condition. For these individuals,beta-blockers can be prescribed to treat the increasedsympathetic activation they experience.^[17]Beta-blockers are competitive inhibitors of adrenaline, thepost-ganglionicneurotransmitter released by cells of thesympathetic nervous system. By blocking the ability of receptors to bindadrenaline,beta-blockers have been observed to alleviate symptoms ofanxiety, increasedblood pressure, and irregular heartbeat, amongst others. Anti-anxiety medications can also be prescribed to individuals with this conditions to treat symptoms ofanxiety.

• Overview at vivo.colostate.eduArchived 2023-05-14 at theWayback Machine
• Thyroid+Hormone+Receptors at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Genes on human chromosome 17
• Genes on human chromosome 3
• Nuclear receptors

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