Meandering thoughts about T4 and T3

[helvella]

Regardless of whether there are T4-specific receptors, or receptors that can be triggered by T4 or T3 (or something else!), there is an issue which is important and documented quite widely.

Our blood stream does not circulate throughout our bodies evenly. Some parts are relatively isolated. The most talked-about is probably the blood-brain barrier (BBB).

For thyroid hormone, any thyroid hormone, to get from the bloodstream into the brain it needs to be actively transported across the BBB. Several active transporter mechanisms have been identified but there is still a lack of complete clarity about them. At one time, it was claimed that T3 cannot get into the brain at all (from the bloodstream) – that appears to have been dismissed, if only from the evidence of people with no thyroid activity who survive, often very well, on T3-only!

Could it be that in addition to acting as a storage reservoir, T4 also helps to get sufficient thyroid hormone to parts which are relatively distant, in a blood flow sense? (The BBB makes the brain more “distant” by requiring transporter mechanisms.) For example, by how much is T3 level reduced between the heart and the toes? The implication of this thought is that distant tissue will likely have to do more of its own, local conversion, because the blood arriving is already relatively depleted of T3. Certainly, hair follicles do. The brain does. Do other distant tissues like finger and toenails?

Perhaps there is a germ of an idea as to why people taking a significant amount of T3 often seem to need what appear relatively large doses?

Have to end my meandering thoughts here – and put a few links. The first one is available in full. The other two are, unfortunately, behind paywalls.

Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters

jme.endocrinology-journals....

Mol Cell Endocrinol. 2017 Jan 24. pii: S0303-7207(17)30042-4. doi: 10.1016/j.mce.2017.01.029. [Epub ahead of print]

The ups and downs of the thyroxine pro-hormone hypothesis.

Galton VA1.

Author information

• 1Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA. Electronic address: [e-mail].

Abstract

Thyroxine (T4) is the major thyroid hormone in the thyroid gland and the circulation. However, it is widely accepted on the basis of abundant evidence that 3,5,3'-triiodothyronine (T3) is responsible for most, if not all, of the physiological effects of TH in extrathyroidal tissues, and T4 functions as the pro-hormone. Whether T4 has any intrinsic activity per se or is merely a pro-hormone that must be converted to T3 in order to exert any TH action has yet to be resolved. Although there are some physiological actions of T4 that are mediated by receptors at the cell membrane (non-genomic effects), the vast majority of the physiological effects of the THs identified to date involve the binding of T3 to specific nuclear receptors to regulate gene expression (genomic effects). This review examines how the role of T4 in genomic TH action has been viewed and debated during the hundred years since it was first isolated in 1914.

Copyright © 2017. Published by Elsevier B.V.

KEYWORDS:

3,5,3'-triiodothyronine; Deiodinases; Thyroid hormone action; Thyroid hormone receptors; Thyroxine

PMID: 28130114

DOI: 10.1016/j.mce.2017.01.029

ncbi.nlm.nih.gov/pubmed/281...

Mol Endocrinol. 2014 Apr;28(4):534-45. doi: 10.1210/me.2013-1359. Epub 2014 Feb 19.

Identification of a new hormone-binding site on the surface of thyroid hormone receptor.

Souza PC1, Puhl AC, Martínez L, Aparício R, Nascimento AS, Figueira AC, Nguyen P, Webb P, Skaf MS, Polikarpov I.

Author information

• 1Institute of Chemistry (P.C.T.S., L.M., R.A., M.S.S.), State University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil; Institute of Physics of São Carlos (A.C.P., A.S.N., P.W., I.P.), University of São Paulo-USP, São Carlos, Sao Paulo, Brazil; National Laboratory of Biosciences (A.C.M.F.), CNPEM, Campinas, Sao Paulo, Brazil; University of California Medical Center (P.N.), Diabetes Center, San Francisco, California; and Genomic Medicine (P.W.), Houston Methodist Research Institute, Houston, Texas.

Abstract

Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many nuclear receptor ligand-binding domains (LBDs) reveal that the ligand binds within the hydrophobic core of the ligand-binding pocket, a few studies suggest the possibility of ligands binding to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T3 and T4 located between H9, H10, and H11 of the TRα LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics simulations to investigate ligand mobility and ligand-protein interaction for T3 and T4 bound to this new TR surface-binding site. Extensive molecular dynamics simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions.

PMID: 24552590

DOI: 10.1210/me.2013-1359

ncbi.nlm.nih.gov/pubmed/245...

[TSH110]

Is this why my toenails are horrible, deformed nasty things that even pliers struggle to snip through and my fingernails lift off the nail bed, are ridged like corrugated cardboard and just bend or crumble? They were lovely before this illness did for them. T4 monotherapy hastened the deterioration, NDT helped...but not much. As for my brain...the less about that said the better 😂😂😂

Excuse my flippancy it is an interesting meander...

[helvella Administrator Thyroid UK in reply to TSH110]

Well, you may say flippancy, but I might say "evidence".

Just have to work out exactly what sort of evidence it is!

[SilverAvocado in reply to TSH110]

Hehe, I agree! My toenails have become like the landscapes in fantasy films. Rather beautiful in a strange way, but now often painful.

[helbell in reply to TSH110]

Ditto, especially my toe nails. And numbness.

[diogenes Remembering]

It's probable that distant organs like toes and finger ends get virtually the same supply of T4 and T3 that organs closer to the thyroid get. This comes about because such a tiny fraction of T4 and T3 is actually free in circulation compared with the total hormones bound to transport proteins. For T4 only 0.02% is free and for T3 0.2%. So on one pass through the circulation throughout the body, less than 1% of the available hormone is used up. When the blood next goes by the thyroid gland, then it is topped up again to its former level. So though differences may exist in T4-T3 conversion in different parts of the body, this is usually due to a mix of receptor concentration and identity of the deiodinase that catalyses T4-T3 conversion. Brain deiodinase can have different properties from other organs. There is also another complication called ubiquitination (horrid word!). This describes the action of a protein called ubiquitin which can attach to and modify deiodinase activity locally according to needs. The whole business of receptor genetics also plays its role. The field is fearsomely complicated.

[diogenes Remembering]

We can work out a rough guide to how depleted distant organs at the end of a cycle of blood flow will have any depletion in T4/T3. 1) It takes about 1 minute for on pass round the body. 2) we know the half life of T4 is about 8 days and T3 1 day. Thus for T4, 50% is lost in 8 days if there is no thyroid replenishment. There are 60 x 24 x 8 = 11520 full passes in that time. Remember on each pass the working thyroid replenishes any depletion. Thus on 1 pass, the T4 is depleted at the last organ before passing the thyroid again by 0.5/11520 (x 100) % or 0.004% (this is negligible). For T3 this will be 0.5/1440 (x100)% or 0.034%. But T3 anyway is made up continuously by conversion, so the effect on T4 may be slightly bigger so as to keep T3 constant, but the T4 effect is still negligible.

[TSH110]

diogenes thanks for that Information it is very interesting

[helbell]

My mind boggles at how we manage to evenly replenish from once daily doses via the gut. Does that mean we just rely on what the liver can put out on demand? And that the liver is under burden because it has to store and supply more than would be normal in continuous conversion. I'm grasping here...Poor brain!

[diogenes Remembering in reply to helbell]

No, the T4 gets quickly distributed into the blood, where the reservoirs for free T4 supply are the circulating transport proteins. It's from these, rather than liver stores that the tissues get their supply. If there is any liver storage it is small compared with the blood load.

[helbell in reply to diogenes]

That's useful to know. Relief, actually. Thanks