Temperature-responsive release of thyroxine and its environmental adaptation in Australians

Qi, Xiaoqiang; Chan, Wee Lee; Read, Randy J.; Zhou, Aiwu; Carrell, Robin W.

doi:10.1098/rspb.2013.2747

Cited by 27 publications

(15 citation statements)

References 34 publications

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“…These findings are interesting from the basic science perspective and point to the fact that abnormal TH values might be explained by genetic defects in TH-binding proteins and must not necessarily reflect diseased thyroid status. The evolutionary significance of TBG and its genetic variants has been highlighted in another recent study on a population of Australian indigenous people, where it was found that certain folds of TBG may contribute to adapting to life in hot climates [12,13]. These recent observations on TBG mutations and altered TH-binding capacities are important to consider in cases where such mutations are prevalent in family history, in order to avoid unnecessary treatment which would otherwise be motivated by seemingly diseased serum TH concentrations.…”

Section: Laboratory Th Assessmentmentioning

confidence: 99%

Understanding the Healthy Thyroid State in 2015

2015

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Thyroid hormones (TH) are of crucial importance for the physiological function of almost all organs. In cases of abnormal TH signaling, pathophysiological consequences may arise. The routine assessment of a healthy or diseased thyroid function state is currently based on the determination of serum concentrations of thyroid-stimulating hormone (TSH), and the TH T₃ and T₄. However, the definition of a ‘normal' TSH range and similarly ‘normal' T₃ and T₄ concentrations remains the subject of debate in different countries worldwide and has important implications on patient treatment in clinics. Not surprisingly, a significant number of patients whose thyroid function tests are biochemically determined to be within the normal range complain of impaired well-being. The reasons for this are so far not fully understood, but it has been recognized that thyroid function status needs to be ‘individualized' and extended beyond simple TSH measurement. Thus, more precise and reliable parameters are required in order to optimally define the healthy thyroid status of an individual, and as a perspective to employ these in clinical routine. With the recent identification of new key players in TH action, a more accurate assessment of a patient's thyroid status may in the future become possible. Recently described distinct TH derivatives and metabolites, TH transporters, nongenomic TH effects (either through membrane-bound or cytosolic signaling), and classical nuclear TH action allow for insights into molecular and cellular preconditions of a healthy thyroid state. This will be a prerequisite to improve management of thyroid dysfunction, and additionally to prevent and target TH-related nonthyroid disease.

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Section: Laboratory Th Assessmentmentioning

confidence: 99%

Understanding the Healthy Thyroid State in 2015

2015

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“…The steady-state concentration of free thyroxine in the blood is ultimately set centrally by the secretion of the thyroid stimulating hormone TSH, but the maintenance of the concentration of the free hormone, at near 20pM throughout the tissues, results from the equilibrated release of thyroxine from TBG. The binding affinity of TBG for thyroxine is exceptionally tight (Kd ~80pM) with TBG acting as a circulating store of the hormone and only 0.03% of the total thyroxine being in the free form in blood [29]. The binding capacity of circulating TBG is only partially saturated, and it is the percentage saturation of TBG, of 20% or more, that by the law of mass action determines the concentration of free thyroxine in the blood.…”

Section: Thyroxine and Cortisolmentioning

confidence: 99%

How serpins transport hormones and regulate their release

Carrell

Read

2017

Seminars in Cell & Developmental Biology

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The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the corticosteroids are transported bound in a 1:1 ratio on almost identical sites in the two homologous binding-globulins, TBG and CBG. Recent structural findings show an equilibrated, rather than on-and-off, release of the hormones from the carriers, reflecting small reversible movements of the hinge region of the reactive loop that modify the conformational flexibility of the underlying hormone-binding site. Consequently, contrary to previous concepts, the binding affinities of TBG and CBG are not fixed but can be allosterically modified to allow differential hormone delivery. Notably, the two carriers function like protein thermocouples with a surge in hormone release as body temperatures rise in fevers, and conversely a large diminution in free hormone levels at hibernation temperatures. By comparison angiotensinogen, the source of the angiotensin peptides that control blood pressure, does not appear to utilise the serpin mechanism. It has instead evolved a 63 residue terminal extension containing the buried angiotensin cleavage site, which on interaction moves into the active cleft of the renin. The conformational shift involved is critically linked by a labile disulphide bridge. The observation of changes in the redox status of this S-S bridge, in the hypertensive complication of pregnancy, pre-eclampsia, has opened an unexpected level of regulation at what is the initial stage in the control of blood pressure.

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“…Furthermore, the peak of these secretory pulses may exceed the saturation of CBG (Cameron, et al, 2010), increasing the height of the ultradian peaks of cortisol. This can effectively magnify the excursion of the pulses (Henley & Lightman, 2011), allowing large pulses of free hormone to occur in extravascular tissues such as the brain and subcutaneous tissue (Qi, et al, 2014). This is of relevance because the ultradian rhythm has been shown to be important in glucocorticoid signaling and gene transcription (Stavreva, et al, 2009).…”

Section: Cortisol and Thyroxinementioning

confidence: 99%

“…Conversely, when the temperature rises above 37 o C, as in fevers, there will be a boosted release of thyroxine, with the equilibrated concentration of free thyroxine at 39 o C increasing to near thyrotoxic levels. Evidence that this potential boost of thyroxine release in fevers is purposeful, comes from the presence in an Australian aboriginal population of an adaptive mutation that turns off the fever-induced acceleration of thyroxine release (Qi, et al, 2014). The mutation occurs within the site linking the immediate point of entry of the reactive loop into the body of the molecule with the adjacent hormone binding pocket (Figure 1b).…”

Section: A Protein Thermocouplementioning

confidence: 99%

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Cortisol and CBG — Getting cortisol to the right place at the right time

Henley

Lightman

Carrell

2016

Pharmacology & Therapeutics

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Cortisol is transported in the blood by corticosteroid-binding globulin (CBG), a non-inhibitory member of the serpin family of serine protease inhibitors. Recent structural advances reveal how CBG acts as a releasing-agent as well as a carrier of cortisol. Taken together, the structures of the various forms of CBG and of the closely related thyroxine binding-globulin, show how the inherent conformational mechanism of the serpins has been adapted to modulate hormone release to the tissues by changes in binding affinities. A deduction from this, of the temperature dependence of hormone binding, is remarkably borne out with CBG, with a doubling in plasma free cortisol as the body temperature rises to 39°C. Another insight, against a dogma in the corticosteroid field, is that the proteolytic cleavage of CBG in inflammation results in a partial and not a complete loss of cortisol binding. This becomes of medical importance in conjunction with recent evidence of a pool of the circulating cleaved-form of CBG. It is now evident that tissue levels of free cortisol are buffered by two responsive plasma pools, intact CBG with a high binding-affinity and, particularly in inflammation and sepsis, a further pool of cleaved-CBG with a ten-fold lower affinity. The new molecular understandings, as well as providing insights into the differential release of circulating hormones, also open prospects for therapeutic interventions and draw attention to the potential of CBG and TBG as vehicles for the targeted delivery of drugs.

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Temperature-responsive release of thyroxine and its environmental adaptation in Australians

Cited by 27 publications

References 34 publications

Understanding the Healthy Thyroid State in 2015

Understanding the Healthy Thyroid State in 2015

How serpins transport hormones and regulate their release

Cortisol and CBG — Getting cortisol to the right place at the right time

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