wed april 11, thyroid hormones continued

overhead shows different T3 and T4, and products that are not made in the thyroid....

that is true depending upon waht you mean by made in the thyroid gland.

RT3 is never incorporated into the thyroglobulin. the only ones you will find attached to the thyroglobulin are MIT, VIT, T3 and T4. RT3 is not made as part of the coupling reaction. once the thyroglobulin is hydrolyzed, by endocytosis, and combines with lysosomes, and permiases hydrolyzed the thryoglobulin then it is possible for T4 to be acted on by an inner ring diiodinase and so within the ep cell then it is possible to make RT3. (RT3 is bio-inactive)

Let's talk about the bio activity of thyroid hormones, and then regulation and secretion of thyroid hormone action. there are 2 thyroid hormones T3, and T4, T3 the thyroid hormone receptor has a much higher affinity for T3 than T4. T3 is there for the biologically the more potent hormone. T4 is a precursor that T3 is made. But if T4 does happen to bind, it does the same action as T3, but it is FAR less likely to bind. the general list of activities of thyroid hormones is sumarized at the bottom of the handout. It should be right at the front.

thyroid activities in mammals:
one of the key biological activites of TH (thyroid hormones) they increase the metabolic activity of most cells. the exceptions here are: not neurons, testes or spleen. when bound metabolic rates increase in the cell because this happens it then increases the metabolic rate in the entire animal. what basal metobolic rate is: minimum amount of activity required to sustain life in terms of metobolic processes. As soon as you eat something your metabolic rate goes up, as with any movement too. in practical terms it is very expensive to shut someone up to find their basal rate, so instead they check their exhale breath for o2 consumption, and they can figure it that way.

if you give someone thyroid hormone it increases their metabolic rate, and it increases for a number of reasons. increase in the number of mitochondria from increased TH. and increases all the levels of enzymes in the mitochondria. also increase the nubmer of sodium/potasium atpases in the plasma membrane of those cells. plus there is an increase in sodium/pot leak channels in the plasma membrane. increased leakage of pot out, and sod in to the cell, with everything trying to maintain the status quo and works that much harder to keep the balance. which increases o2 consumption which by definition is an increase in metabolism.

plasma membrane always contain sod/pot channels that are called 'leak channels' the electo-chemical gradiant drives it. the atpase pumps the sodium back out, and the pot back in. increasing the leak channels and atpase you are just speeding it all up and running it more times for higher metabolism.

another thing TH do, is they have a large effect on intermediary metabolism. there are numerous effects and what makes it confusing is the effects are dose-dependant. what happen is that the TH effect most if not all of the major metabolic pathways. TH increase lipogenesis, and lipolosis (break down), and they increase protein synth but they can also increase proteolosis depending upon the dose. if you look at those together, usually what happens is that if the TH is too high then there is a net catabolic effect. you tear down more than you make. in the case of carb metabolism TH increase and stimulate gluconeogenesis, glycogenolysis, and depending upon the dose, stimulate glycogen synthesis. if it is too high the net effect is an increase in glucose concentration. if you look at this, TH stimulate anabolic and canabolic pathways, which means if you increase the TH you make things faster and you tear them down faster, you increase more you run it even faster. if it is really high they cycles become futile cycles, you make it and tear it down. net effect: there can be an increase in futile cycles as TH concentration increases.

one of the reasons this is important is that it leads us to the next bio activity of TH which is to increase heat production in the body. the more chemical reactions taking place, means more heat. also due to an increase in the synth called uncoupling protein (aka thermogenin?) (final step of atp synth, adp phosphorylation to atp occurs in the mitochondria. because of the activity of the e transport chain there ends up being a high concentration of protons in the intermembrane space. the proton gradiant is important in atp production because it drives the activity of the enzyme that converts adp to atp. enzyme is called atpsynthase. because of the concentration between space and the inner mit space, the protons move through the atp synthase and that allows adp to be phos'd into atp. without the protons moving through and interacting with the atpsynthase the atp doesn't' get made. what the uncoupling is basically a proton channel that is present in the inner mit membrane, and when it is open, protons don't necessarily interact with the atpsynthase. they can go thru the wide open channel, and atp isn't produced. the cell went through a great deal of trouble to make a proton gradiant, and heat, but is wasted because it bypasses the gradient and doesn't make atp. With more TH, you make more heat, but nothing to show for it. TH make the creation of more H channels. The net effect is that if you increase TH, you increase number of futile cycles, and rate, to generate heat, and thermogenin (uncoupling protein) which produces a lot more heat. TH goes up, and you feel warm. this effect is an increase in heat production due to TH is called the thermogenic effect of THs.

these two effects (increase in met rate, and heat production) are the universal effects of TH in mammals. they also regulate a number of other pathways too. TH has a very long half-life in the circulation that takes several days to get a peak response. other effects of TH we can put in the developmental catagory, and are extremely important. such as effects on the CNS. during development THs do several things within the nervous system. theyincrease milanation of axon, and increase nerve growth, and increase dendridic branching, and regulate neuronal migration.

milan sheet wraps around axons and acts as an insulator, and keeps ionic current from leaking out. the net effect is that a milanated axon conducts aaction potentials much more rapidly than an non-milinated axon. babies are not coordinated because their axons are not milinated. adults are fully milinated and so are super quick. dendritic branches, the input part of the neuron consists of the cell body and the dendrite. dendrite is where most synapses in the nervous system occure. branches occur so that you have lots of places to connect.

neuronal migration is important because they move through the nervous system, and without the movement you don't develop normally. without T3 and T4 at birth, within 2-3 weeks from birth, there is profound and permanent mental retardation happens. they check blood if babies are born in hospitals, to make sure your thyroid is good. it isn't correctable if it isn't caught right away. the mother gives some TH, but still there could be developmental issues because it isn't enough.

the other time that THs are important is that they increase alertness and wakefulness. If it is too low in adults, the net effect is lethargy, and a mental slowness. another important effect is it is needed for normal body growth. and this is true because TH increase GH secretion and TH increase GH receptor expression. GH is required for post-natal growth. in addition TH stimulate bone maturation.

also needed for normal reproductive production. and if you look at symptoms of hypo/hyper thyroid there are problems with the mentstral cycle. there is no clear explanantion. but pretty much everythign seems to be effected by the TH, and it triggers cascades that mess up reproductive function.

the TH increase the sensativeity to epi and nor-epi. it does this partly by increasing expression of ?beta-adanergic? receptors. the net results is that you get an increase in heart rate and cardiac output. This is a permissive effect. Epi and nor-epi are adrenalin and nor-adrenalin, which are major regulators of the heart. if you raise those concetration it causes heart rate to go up, and cardiac output to go up (volume of blood pumped every minute). Ordinarily they increase heartrate and cardiac output. TH increase expression of epi and nor-epi receptors in the heart. For them to act on the heart there has to be a receptor for it to bind to. the adranergic receptors are what bind the epi and nor-epi. the more recpetors there are the more the effect is on the heart. if there were no adranergic receptors in the heart, the epi and nor-epi could not effect the heart at all, no matter the concentrations. this is called a permissive effect because with the TH itself, you aren't aware it is going on, by stimulating the increase of adranergic receptors, 'gives permission' for epi and nor-epi to act on the heart. hormones work in the background to regulate expression for another hormone, and allow it to do its thing. besides increasing expression of these receptors, there is also a direct effect on the heart that increase heartrate and cardiac output directly from the TH itself.

REGULATION AND THYROID HORMONE SECRETION
look at the pathway on the handout.
the hypothalamus secretes thyrotropin releasing hormone into a capallary bed in the median eminans, blood carries it through portal vessels, down to the pit gland where it exits a capillary bed and if it binds to a thyrotrope it stimulates secretion of TSH and then is released into the circulation. if it gets back the the thyroid gland it binds to the phelicular epithelial cells stimulating T3 and T4 from the thyroid folicles.

in terms of TRH stucture, it is a tripeptide. it is very simple. the book tells you the aas there are, but you don't need to know that. expect TRH to be a pro-hormone because it is so small. pro-TRH is hydrolyzed to yeild 6 molecules. TSH belongs to a family of hormones called the glycoprotein family. that means all the members of the family are very similar. members of the glycoprotein family there are 4 members: TSH, FSH, LH, (pit products), Human colionic gonadatropin HCG (produced only during pregancy in the embrio). these molecules are glycoproteins (they are glycosolated) and they consist of 2 subunits (alpha and beta). they combine to mol weight of 30K. so each subunit is a single polypeptide chain, plus glycosolation (plus sugar). the 2 subunits are non-covalently associated. if you look at the alpha TSH/LH/FSH/HCG they have identical AA sequences. alpha is always the same in that family. there are some differences in glycosolation. the beta subunits are totally unique to each hormone. the beta subunit confer receptor specificity. whatever beta subunit there is, it will only bind to its appropriate receptor. LH to LH receptor, etc. the alpha needs to be there for necesary for signal transduction.

the glycosolation is important because it increases the half-life of the hormone in circulation. (30mins to an hour or so). glycosolation protects against endomatic degradation, but does not keep it from being excreted in the urine (that is how a preg test works). TRH can also stimulate prolactin creation. in the pit gland which cell it binds to dictates what happens next. the TRH molecule doesn't have a choice. It is the minor prolactin regulator. thyrotropes: TSH secretion, or lactotrope then prolactin secretion. It is totally random as to which cell it binds to.

TRH is the major regulator for TSH secretion. in terms of TSH inthe thyroid gland, it does alot of different things. it increases iodine uptake from the extracellular fluid, by increasing expression of iodine transporters. it increases thyroglobulin synthesis, and increases iodination of tyrosine, and increases coupling of iodinated tyrosines, and stimulates endocytosis of choline, stimulates cytoglobulin proteonlosis, stimulates activity of thyroid peroxidase, and it them overall stimulates folicular cell hypertrophy, and hyperplasia. TSH stimulates every part of the pathway making thyroid hormones, except of moving iodine from inside of the epithelial cells into the coloid. that will happen without TSH. TSH upregulates every other part of the TH making process. in addition to that it stimulates hypertrophy, and hyperplasia of the cells that make up the folicles. hypertrophy means one cell gets bigger, hyperplasia means an increase in the total number of cells. just by making more TH producing cells means you get more TH.