Evolution of Nuclear Receptors and Ligand Signaling: Toward a Soft Key-Lock Model?

[helvella]

OK folks, so you thought you'd got your head around thyroid hormones. You really have done a lot of reading. You recognise all the abbreviations and technical terms. You think it all hangs together.

Then someone throws in another idea - one that potentially adds another order of magnitude of complexity...

I can't tell you what I'll say if a doctor ever tries to tell me that hypothyroidism is simple...

Curr Top Dev Biol. 2017;125:1-38. doi: 10.1016/bs.ctdb.2017.02.003. Epub 2017 Mar 25.

Evolution of Nuclear Receptors and Ligand Signaling: Toward a Soft Key-Lock Model?

Holzer G1, Markov GV2, Laudet V3

Author information

1 Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, Lyon Cedex 07, France.

2 Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR 8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, Place Georges Teissier, Roscoff Cedex, France.

3 Observatoire Océanologique de Banyuls-sur-Mer, UMR7232, Université Pierre et Marie Curie, Paris, Banyuls-sur-Mer, France. Electronic address: [e-mail].

Abstract

Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that modulate a wide variety of physiological functions in a ligand-dependent manner. The first NRs were discovered as receptors of well-known hormones such as 17β-estradiol, corticosteroids, or thyroid hormones. In these cases a direct activation of the receptor transcriptional activity by a very specific ligand, with nanomolar affinity, was demonstrated, providing a strong conceptual framework to understand the mechanism of action of these hormones. However, the discovery that some NRs are able to bind different ligands with micromolar affinity was a first sign that the univocal relationship between a specific receptor (e.g., TR) and a specific ligand (e.g., thyroid hormone) should not be generalized to the whole family. These discussions about the nature of NR ligands have been reinforced by the study of the hormone/receptor couple evolution. Indeed when the ligand is not a protein but a small molecule derived from a biochemical pathway, a simple coevolution mechanism between the ligand and the receptor cannot operate. We and others have recently shown that the ligands acting for a given NR early on during evolution were often different from the classical mammalian ligands. This suggests that the NR/ligand evolutionary relationship is more dynamic than anticipated and that the univocal relationship between a receptor and a specific molecule may be an oversimplification. Moreover, classical NRs can have different ligands acting in a tissue-specific fashion with significant impact on their function. This also suggests that we may have to reevaluate the pharmacology of the ligand/receptor couple.

© 2017 Elsevier Inc. All rights reserved.

KEYWORDS:

Alternative ligands; Evolution; Ligand; Nuclear receptors; Pharmacology; Phylogeny; Retinoic acid; Steroids; Thyroid hormones

PMID: 28527568

DOI: 10.1016/bs.ctdb.2017.02.003

ncbi.nlm.nih.gov/pubmed/285...

[Justiina]

I give up.

I was just on phoneixrising forum and oh my that stuff depresses me and I want to give up. I can tolerate some level of thyroid issues and complexity of it is already knocking me out.

But this stuff now is ridiculously HC or maybe it's because English is not my first language and scientific jibberjabber twists my brain so bad I can hear it's clicking.

[Kitti1 in reply to Justiina]

😂😂👍

[Saggyuk in reply to Kitti1]

Yep, definitely a new one on me lol. I think they do it on purpose like legal stuff to ensure the general population continue to believe it is over their heads and they are therefore required when one has issues. I learnt legal stuff and I'm damn sure I will understand all this stuff too so will read everything.....just maybe at a later date

I would be interested to know how many medically qualified GPs could understand.

However, I should also note that no matter how much I read, I certainly will require a surgeon should ever the need arise

[helvella Administrator in reply to Justiina]

Seems to me that you need someone to point out that your English is at least as good as most of us. Most of the time the only give-away is that your name has the double-i which is pretty rare in English.

But yes, some of it is so incredibly hard to get our brains around. Even if we understand the mechanism, the actual links, it is much harder to take that in so that we see how it really works in practice.

There are many oddities that occur in the much simpler world of physics and mechanics. Many have been exploited as toys or conjuring tricks - or just "Would you believe this?" pictures. There must be similar features in any complex system, including thyroid.

This is why, at the end, there seem to be just two ways of handling this.

1) Develop computer modelling, tailor that to the individual, and use that to dose. Possible with a directly controlled hormone dosing implant.

2) Do the best you can and rely on how patient feels with tests acting as long-stops to help ensure we don't go too far either way.

[Justiina in reply to helvella]

Thanks. English should be third language as Finland is bilingual and Swedish is mandatory, but I have skipped all Swedish classes as well we just hate Sweden and Swedish But I have studied some Russian, Swedish and now Norwegian, despite being ill I have very great memory , my vocabulary is large. I do not often even realize how my words I know/remember! Its overwhelming! I am also a reader, during my life I have read approximately 2000 to 3000 books, hard to know as i have not written them down, but if I read 3 books in a week and started reading at age of 6 then its quite a lot of books during past 32 years.

Sometimes I fear I will fry my brains reading so much and on top of that trying to absorb all these studies and research in foreign language. Ofc being ill has it make it hard to concentrate and its sometimes real struggle to understand even simple text. But I crave for information, I used to crave junk food, now its information

But back to part 1 and 2. I have the idea such a computer program is being developed, not in that scale , but a program that doctor can use to compare different results and notice even slightest changes. I think it was Diogenes who mentioned about it, quite long time ago, my memory is not the sharpest.. ehhheheh, bad one... The issues was that doctors might not want to use it.

[helvella Administrator in reply to Justiina]

Yes - simulation software does exist. If used to illuminate and navigate treatment options it could be excellent. Trouble will be when people are forced to align treatment because the simulation says so. Any simulation, however good, will be imperfect.

[Justiina in reply to helvella]

True, but common sense saves the day. Tho I am not sure how much common sense any doctor has...

[TSH110 in reply to helvella]

@helvella or just keep taking the NDT! For all this amazing scientific knowledge and advance in understanding the first ever treatment using something nature makes in a real thyroid gland - albeit a pig's - seems best suited as a replacement treatment for me. I sometimes think it is a case of science actually getting so removed from the problem it becomes the problem - does looking at things at a microscopic level really help with the bigger picture? Maybe in the future when the current unimaginative mono vision "specialists" have cocked up their toes and a fundamental swing has taken place to thyroid medicine being an exciting area of medicine full of opportunity for novel treatments and helping patients who actually feel well again...not some poor relation to diabetes that a levothyroxine pill and a TSH reading can fix with symptoms thereonin being all in the mind of the patient. How darn unenquiring and dull are they with that as their mantra? Sadly I will probably be ashes when dawn of endocrine enlightenment breaks. I guess it's NDT for me till close of play, but I do feel bad for the pigs dying so I can live a quality life.

[JGBH]

The latter option... am very afraid.

[JGBH]

HI delicious21,

No idea in truth... but let's face it, anything that can help in saving money by any means will be "recommended"... and to hell with patients... as long as the various organisations do not upset each other.

Perhaps the BTA do not want to ruffle feathers by challenging the GMC.... It does seem that BTA is not doing a great deal for patients who have thyroid problems ... No doubt someone will come up with a god reason... I hope. Sorry can't answer your questions.

[Saggyuk]

Haha, I'm not sure they want to understand lol! I don't like to regurgitate, I like to visualise how anything works in pretty little body/metaphoric pictures with cute cartoonish characters interacting and saying hi to each other (or punching/eating) and work out how it fits with everything so I can ponder how linked to everything else and more importantly so I can argue if a doctor says some crap about how not the case and tries to throw me off the case with unknown words lol - Now I just got to try and conjure up some new characters and fit this into my slightly somewhat non-functioning brain lol

[Angel_of_the_North]

Why would the GMC care if we are ill? It's an organisation to protect medical professionals from patients. And doctors get paid whether we are ill or not, and are deemed correct as long as they follow NICE guidelines - any colour as long as it is black; personalised medicine is far too expensive.

[Angel_of_the_North]

They did really well with Harold Shipman, didn't they?

In a clinical dissection of its failings, the High Court judge Dame Janet Smith, who chaired the inquiry, said despite efforts to change, the organisation remained too reactive, with a culture described as something between an old boys' club and a trade union for medics.

"The old culture of protecting the interests of doctors lingers on for the majority of GMC members," Dame Janet said. "A significant change of culture is necessary ... However, I do not feel confident that it will do so."

They get rid of doctors who cure their patients as individidauls, but don't toe the party line (like Dr Skinner) and support the old boys against whistle blowers like Rita Pal.

Buck the trend and you'll be investigated whether your patients value you or not.

[Angel_of_the_North]

Long ago depends on your age. Rita Pal's experience is recent and the ?Hooper report was just smarmy words. Think of Dr Myhill's experiences - luckily they tried to strike her off for acting as a midwife to a PIG, which made them look so stupid they had to back down!

"Despite prosecuting Dr. Myhill for ten years, a necessarily stressful and time consuming business for her, the GMC remain unrepentant. It appears that the GMC has no inclination to correct its ways, or to try to restore Dr. Myhill’s professional reputation."

“Most doctors don’t listen to patients and don’t want to consider views that undermine their authority. They just look at patients from behind their half-moon glasses and say, ‘Don’t worry your little head about it.’ ” Dr Myhill