wed, april 18th: disorders of the thyroid hormone

Last time we talked about the mech of TRH action and TSH action, and both of those receptors are 7trans-serpantines that are coupled to G proteins. those 2 hormones when they bind to the specific receptor, they stim the associated the G protein and actiavte one of the pathways that we talked about. TSH activates primarily the Gf pathway and which stims the adenyl cyclase activity and results in an increase is cAMP in the cell, which increases the activity of protein kinase A which leads to various cellular effects like changes in the enzymes activity or rates of gene transcription. TRH receptor is coupled to Gq that acts when TRH bind it activates activity of phosopholypase C-beta which results in an increase in phosphoinostitol concentration which triggers an increase of Ca2+ in the cells which inc. diacyl glycerol levels and protien kinase C activigty which regulates enzymes and gene expression.

the last thing we talked about what the mech of acgtion of thyroid hormone, and a genomic mech of action. that refers to a thyroid hormone receptor acts as a transcription factor. it regulates the rate of gene expression, and that whole idea that a hormone enters a cell and interacts with a receptor that is bound to the regulatory region of the gene, and that complex regulates transcription is considered a 'genomic mech of action' for thyroid hormones and steroid hormones. this term you should know.

Some people refer to this as a classical mech of action, for steroids and thyroid hormones. (see handout) the hormone plus receptor acts as a transcription factor that regulates gene expression. This mech of action where there is an intracellular receptor that acts as a transcription factor. this is the first one discovered for steroid hormones and later realized that it was shared with thyroid hormones.

The other way that steroids and thyroid hormones work is taht they bind to specific receptors in the plasma membrane, and to distinguish that from the genomic reaction is called 'non-genomic' or non-classical mech of action. in this case the thyroid hormone receptors are in the plasma membrane, and are physically diffderent proteins as you would find associated with dna. there is some proof that the thyroid hormone receptors are G protein linked
. the major differnt in concept: if you ahve a hormone, it has to get into the cell, find the receptors, ditch corepressors, get coactivators, etc.... is slow like 30-60mins to see your transcription of a protein, acting as a transcription factor for antoher gene to be transcribed and thaty might be the end....

the non-genomic mech of action you see in just a few minutes.... all that has to happen is that they thyroid hormone binds to the receptor you activate the G protein, and then signal transduction cascade and that's it!

That last thing we are going to talk about then in terms of hormone mech of action are conceptual things....
Terms:

Agonist: a compound that binds to a hormone's receptor, and evokes a response that is both qualitatively, and quantitavely similar to that evoked by the actual hormone.

There are many drugs that act in this way (agonist) like a synthetic estrogen, that bind in the same way as the natural versoin.

Antagonist: the opposite. A compound that binds to the receptor, but then blocks activity, such as compettive inhibitors, or allosteric inhibitors. (allosteric: drug binds somewhere other than the binding site, that forces a change in the binding site)

Also partial-agonist or partial antagonist, bind, but the response is smaller, and so they block the full response from happening.

last page of handout?
the basic interaction is: hormone binds to the receptr yeilds the hormone receptor complex. it is reversable and noncovalent. we can define:
Kd: dissociation constant
Ka: association constant (they are inverses of each other)
You can see how the math works, it is the same as the equilibrium constant from biochem.

either of these terms refer to the affinity of the hormone receptor interaction. affinity is defined as a tendancy of the hormones to bind to the receptor. if you have a hormone receptor interaction has a high affinity then it moves to the right. High affinity: Kd is small, and Ka is large. for hormone receptor interactions to seem physiologically meaningful, it needs to be on the 10-8 molar or smaller. The equilibrium is strongly in favor of the formation of the hormone receptor complex. if it is lower than 10-8 (kd is greater, or ka is smaller) then you can demostrate mathmatcially that what is formed is so low that the physiological response is negligable.

The reason is that the lower the affinity, the greater the concetraion of hormone has to be in order to get a response.

In terms of what is important to the cell, you can demostrate that the biological response is directly proportional to the concentration of hormone receptor complex that forms in the cell. if you have lots of hormone bound to the cell , than if you have less bound. as you increase hormone concentration, you will drive the reaction towards making hormone receptor complex. If the amount increases to its max level, it tops out. the concentraiont of the hormone recptor complex is important in terms of the magnitude of the physiological response you will get. you can change the concentration by changing anything on the right hand side of the equation. if I increase hormone concentration that will drive it toward making more HRC. if I increase hormone receptors concentration, it increases the hromone receptor complex. if I increase the affinity of the hormone receptor interaction, that will also increase the HRC. But there is a plateau that can be reached.

When the affinity of a reaction become too low, as that number (Ka) gets smaller you will get less and less product. What people have determined experimentally, when the Ka gets below 10-8 molar yo udon't get product any more. so people need to know what the receptor is for a hormone, and if it is too small they will not consider it a relavent receptor. If H and R are both huge you can drive the way to the left, which allowws you to compensate for a low Ka. There is also a saturation effect, where they are finite, and one of the criteria is high affinity for the hormone, and that there are only a finite number of receptors. if you it were linear, then yo uwould know you aren't binding it to the cell.

These things change by altering, affinity of receptor, receptor concentration , and hormone concentration. lets look at changes in hormone concentration: peptide or protein, or hormones or amines. you can chagne the concentration of hormone in circulation by either increase/decrease the rate of synth, inc/dec rate of release of hormone, or inc/dec the clearance rate. if you change any of these things, then the concentration of hormone in circulation changes. in the case of the steroid hormones, all of these things apply except there is no regulation of hormone release because steroid hormones are not stored in the cell. If you are looking at the effects of TRH on thyrotropes (in an episodic or fulsityle manner by hyperthylamic neurons), so whenever a load of it hits the ant.pit there is an increase in hormone TRH concentration in the vicinity of the target thyrotrope which drives the reaction to making more TRH and TRH recptor complex, which triggers phosphyanostitol pathway inside the cells which leads to an increase in TSH secretion. the number of receptors in a cell can change, and this can be either up or down regulated. up regulated or down regulated is the language for the receptor concentration in cells. it can happen over the space of days... so one hormone can trigger the synthesis of receptors for another hormone... such as when we spoke of: thyroid hormones stim's that synth of beta-adanergic receptors in the heart. thyroid hormones up-regulate the concentration of beta-adanergic receptors in the heart. some hormones if present in constant amounts for hours or days down regulate expression of your own receptor, after a while the receptor concentration goes down because it was bombared by that hormone for a long time. This kind of thing keeps the cells from burning out. it is self-limiting mechanism if it is bombarded for too long. you can alos have short term changes in receptor concentration where a hormone will bind to a receptor and the complex will be internalized by endocytosis as to end the response. each target cell is different and each hormone is dfiferent.

The last part of this is changing Ka. It works at a few different levels. one of the things that can happen is if you have individuals whose receptor has ungone mutation, if that mutation is in the wrong part of the receptor, it can change the affinity of the hormone receptor interaction. Or a mutation in the hormone, can change the affinty too. other times you might see a change in the affinity of the receptor for the hormone, would be the hormone binds to the receptor which triggers the signal transduction pathway, and one of the enzymes triggered in the STP comes back and phos's the receptor. a phos'd receptor might have a lower affinity than a non-phos'd receptor. the final thing is that receptor affinity differs for different members of a class of hormones. an example of this is: there are 3 naturally occuring estrogens: 17beta- estrodiol, estrone, estriol. estrodiol is the most potent of the three. it is considered the most potent because the estrogen receptor has a much higher affinity than with the other two. If you compare estrone affinity is about 12 fold lower than for estrodiol. It is even lower for estriol. so here you have one class of estrogen receptors but the affinity of the receptor is different for which one you are talking about. ka*estrogen*est-rec -> ERC.... the bigger the Ka, the greater the ERC produced.

about Kd..... this is harder to conceptualize than Ka. unfortunately most literature is listed as Kd, not Ka. the reason for that is that Kd is the hormone concentration at which 50% of the receptors are filled/occupied by hormone. that is a convenient thing to know. (look at handout)

Usually if you are trying to charaterize a receptor, you have done all the work, then the receptors are considers physiologically relavent if the receptor Kd is of within the same order of magnitude as the concentration of the hormone. If the receptor is it 10^-9 and the hormone is at 10^-12 then by comparison the hormone is irrelivant, and conversely if the concentration of the hormone is higher by more than one magnitude, will always drive the reaction to fill the receptors, and there would be no regulation.

Thyroid hormones in disease....
In terms of definitions:
euthyroid: normal conditions.
hypothyroid: thyroid hormone concentration is too low
hyperthyroid: TH is too high
Goiter: enlarged thyroid gland regardless of cause

Let's start with hypothyroidism in adults: signs and symptoms: they will always be cold, and cold intolerant, typically they suffer from fatigue (hyper can too), because thyroid hormone has an effect on the central nervous system that are hypo, they think slow, their heartrate is lower than normal, there is an increase in polar molecules in extracellular space which attacts water, which leads to adema (general puffiness)(generalized myxadema: associated with a thyroid problem), they also have dry skin, and sometimes fowzy hair (dry, over-permed looking), and because they are cold, it drives up periferal vazoconstriction which drives up total periferal resistance, but the decrease in heartrate combats that, so mean arterial pressure doesn' t change that much. Also in hypothyroidism there is an increase in plasma cholesterol, because of a decrease in cholesterol clearance. this leads to cardiovascular disease.

hypothyroidism in children there is a profound mental, and growth retardation. this condition in children is called Cretinism. in utero they get it from the mom, but once born they would need to be supplimented with it. even if it did cross through breastmilk, it doesn't compensate enough for the low production. there is a lack of mylination, and dendrick sign formation, and decrease in formation of synapses, and neuronal migration patterns early in development. They test in the US to see if people can digest phenylalanine, and to make sure they are producing enough thyroid hormone. some people even believe that if you aren't making enough in the womb, that it isn't enough to suppliment after birth.

(endemic cretonism) refers to a lack of iodine in the diet, but creton means hypothyroid.

thyroid lowers production of polar molecules in extracellular space.

pictures: a goiter, someone who's thyroid is massively enlarged (can be either hyper/hypo)