I went to delete this blog because it is so old and discovered that THOUSANDS of people have read it. Okay. I guess it is helping someone:) If it is helping you, please feel free to paypal/googlewallet me some money:P ismirth at gmail dot com
Just sayin'! Thanks:)
Monday, August 18, 2014
Wednesday, May 2, 2007
wed may 2, epi/norepi from AM
Epi/NE increase heart rate and inc contractility to increase cardiac output.
E/NE also increases vasoconstriction which increases peripheral resistance (blood vessels down stream of the arteries constrict, so their diameter gets smaller, so bloodflow exiting goes down, which increases bloodpressure).
If we put both of these together Blood Pressure (or mean arterior pressure MAP) (MAP is the product of cardiac output times peripheral resistance), so if we increase sympathetic NS activity, that increases cardiac output, increases perf resistance, which increases MAP.
Somebody suffering bloodloss, BP falls (MAP falls), to compensate for BP drop, increase in sympathetic NS stimulation, increases Epi/NE release, inc cardiac output, inc perf resist, inc in MAP.
You should have a good uncderstanding of the aqnate=amony of the symp neurons and the AM, draw the biosynth pathway including structure and enzyme names, what all the acronyms mean, and understand in preinciple what will happen to metabolic, and nervous systems when increase decrease of epi/norepi.
E/NE actions on the respritory system:
1) bind to beta-adrenergic receptors in the smooth muscle of bronchials (part of the tubing that carry air to the lungs). when it binds to the beta-adren. rec. it leads to smooth muscle relaxation, which increases the diameter of the bronchials, which decreases the resistance of air flow, and greatly increase air flow. albuterol is a beta-adrenergic binding agent that causes relaxation to open air flow into the lungs of asthma people.
2) E/NE raise arousal (you become more alert), regulate the secretion of a bunch of hormones such as renin secretion and inhibit insulin secretion.
3) E/NE increase metabolic rate and they increase thermogenesis. they increase the activity of outer-ring deiodinase in brown fat. that increases thyroid activity, by converting T4 into T3. Brown fat looks brown because it contains lots of mitochondria, and is the site of non-shivering thermogenesis. T3 stims synth or expression of the molecule thermogenin that is a therm0protein that uncouples from atp generation. they increase lypolysis, and triglyceride breakdown in fat, which increases the fatty acid concentration in fat, that increase opens the proton channels (the thermogenins). if you have an increase in the more active thyroid hormon, that sets it up to make more thermogenins, and they in themselves are closed. they can be regulated. if nor/epi are high, they are open and you have a rapid ability to gen more heat.
steroidogenesis.... You need to learn the boisynth path for these.... (on handout)you need to be able to draw all of the structures, and enzyme names, and patheways. you have to know everything on the sheet.... The parent of all of them is cholesterol. Part of it is chopped off and yo uare left with a ring structure with certain functional groups attached. If you count up thenumber of carbons in all of them, the first three are all 21 C steroids, the last 2 have 19, and then 18. Those are the natural versions, and they synthetic/man-made have different numbers. But you can count the number of carbons in the naturals to tell what the bioacti will be.
What is made hs to do with what enzymes are expressed in any particular cell, and no cells make every single steroid. If something goes wrong in the pathway, that influences other things being made in the pathway.
The way the handout works is it starts with cholesterol (you can look at another handout of cholsterol with a nomenclature of steroicogenic enzymes), and it shows the first structure of the pathway (prenenolone vs cholesterol, the side chanin is cleaved from pregnenolone to make cholesterol). You will want to mem prenenolone, and then memorize the numbering system fof the carbons. if you mem that scheme and then you learn the anems of the enzymes, you can figure out what the next structure cdown the line will look like. if you don't do that and you just go for mem them, you will probably drive yousrlf nuts. they loook too similar to each other.
the second part of the second sheet, gives all the enzymes with multiple names shown. We are going to use the 'trivial names' because they tell what it is actually doing. 17-alpha-hydroxylase; 17, 20 lyase: that tells exactly what it does... adds an OH at 17, and cleaves between 17 and 20.
There are 5 classes of steroid molecules:
Progestins
glucocorticoids
mineralocorticoids
androgens
estrogens
You want to look at the chart and id stuff you already know. At the lower left are mineralocorts ( lower left three)(aldosterone, corticosterone, and beta deoxycortosterone). next to that is glucocorticoid (2), the theird column (all ) is androgens. and the three to the far right are estrogens.
the way the enzymes work is tricky. the enzyme arrows point to what it catalyzes. If it doesn't go all the way across, then it doesn't make that item.
dezmolase is called 'side chain cleavage enzyme', 3 beta...(directly bleow it) goes by the name 3 beta hydroxy steroid dehydrogenase (3besta-hsd). it acts on carbon 3 to an OH, and something else.
and the lowest left enzyme is called aldosterone synthase (makes aldosterone).
The four major steroidogenic tissues testes, ovaries, adrenal cortex, and placenta.
You will run into 'peripheral conversion of steroids', means that step doesn't take place in a traditional steroidogenic tissue (like maybe body fat instead).
Let's talk about where they get cholesterol from, and what is the rate limiting step:
Cholesterol sources: some steroidogenic cells synth it from scratch from acetate. Most of the time, most of the cholesterol comes from the blood in the form of LDL (low density lypoproteins) they take them up, and use the cholesterol that is part of the LDL. uptaek is a place that steroidogenesis can be regulated. sites of steroid synth iwithin a cell... in either the mitochonodria, or in smooth ER. the cholesterol, and all of the subsequent molecules are shuttled between them. Smooth ER is called that because it doesn't lots of ribosomes attached. Ribosomes aren't needed for steroid synth. Steroids are not stored inside the cell. Cholesterol is processed through the pathway, it is highly lipid soluble, and goes right out of the cells. There are no vessicle storage of steroids. there is no way to regulate its release once it is made. If we look at the rate limiting step in the pathway, it is right at the beginning... it is the cleavage of the side-chain from cholesterol. It turns out that side-chain cleavage enzyme is in the inner mitochondrial membrane, and getting cholesterol to the inner mit mem is what makes it the rate limiting step. There is a protein repsonsible (StAR): steroidogenic acute regulatory protein, and it somehow fascilitates shuddling of cholesterol between the inner and outer mit mems. People with a mutation in StAR form little or no steroids. All of the regulatory pathways taht we are going to talk about, all of them act on StAR, as well as all the other enzymes in the pathway.
Last part of the general stuff: mech of steroid action... (handout in class)
Nuclear hormone receptor family... steroid receptors are part of that family. they jhave a hormoen binding domain and a DNA binding domain. thyroid hormones work differently than the steroids do. the thyroid response cell works in a dimer, binds, corepresors replaced by coacts. this is different. the basic concept is at the tope of the sheet.... read sheet. (fig 3-8 from je friffin and SR ojeda) availabel on eres) and fig 3-11 JE Griffin and SR Ojeda.
This is true for all of the molecules on the big pathway for steroids. there are distinct receptors for everything, but with some overlap between mineralocorts, and glucocorticoid receptors.
Adrenal cortex:
looks like a piramid with the inner part being the medulla. there are layers around the medulla (3 layers). the outer layer is called the zona-glomerulosa produces aldosterone; middle layer is called zona-fasiculata; innermost layer is zona-reticularis, both of which produce glucocortocoids and androgens. An easy way to remmber this as GFR from the outside in. (same acronym as from kidneys)
the ZGA layer is the only one that expresses aldosterone synthase. the products of the inner 2 are: androgens: androstenedioe, and DHEA (both are considered 'weak' androgens' which means they ahve relativly low affinity for receptors, not much testosterone or dihydortestosterone, and extermely little estrogens); and specific glucocorticoids: cortisol and corticosterone, these 2 are the most important in humans.
Glucocorticoids: (hypothalamic-pit-adreanl axis handout)...CRH: cortico releaseing hormone if there is no CRH then the pathway shuts down.
A stressor activiates this pathway.
E/NE also increases vasoconstriction which increases peripheral resistance (blood vessels down stream of the arteries constrict, so their diameter gets smaller, so bloodflow exiting goes down, which increases bloodpressure).
If we put both of these together Blood Pressure (or mean arterior pressure MAP) (MAP is the product of cardiac output times peripheral resistance), so if we increase sympathetic NS activity, that increases cardiac output, increases perf resistance, which increases MAP.
Somebody suffering bloodloss, BP falls (MAP falls), to compensate for BP drop, increase in sympathetic NS stimulation, increases Epi/NE release, inc cardiac output, inc perf resist, inc in MAP.
You should have a good uncderstanding of the aqnate=amony of the symp neurons and the AM, draw the biosynth pathway including structure and enzyme names, what all the acronyms mean, and understand in preinciple what will happen to metabolic, and nervous systems when increase decrease of epi/norepi.
E/NE actions on the respritory system:
1) bind to beta-adrenergic receptors in the smooth muscle of bronchials (part of the tubing that carry air to the lungs). when it binds to the beta-adren. rec. it leads to smooth muscle relaxation, which increases the diameter of the bronchials, which decreases the resistance of air flow, and greatly increase air flow. albuterol is a beta-adrenergic binding agent that causes relaxation to open air flow into the lungs of asthma people.
2) E/NE raise arousal (you become more alert), regulate the secretion of a bunch of hormones such as renin secretion and inhibit insulin secretion.
3) E/NE increase metabolic rate and they increase thermogenesis. they increase the activity of outer-ring deiodinase in brown fat. that increases thyroid activity, by converting T4 into T3. Brown fat looks brown because it contains lots of mitochondria, and is the site of non-shivering thermogenesis. T3 stims synth or expression of the molecule thermogenin that is a therm0protein that uncouples from atp generation. they increase lypolysis, and triglyceride breakdown in fat, which increases the fatty acid concentration in fat, that increase opens the proton channels (the thermogenins). if you have an increase in the more active thyroid hormon, that sets it up to make more thermogenins, and they in themselves are closed. they can be regulated. if nor/epi are high, they are open and you have a rapid ability to gen more heat.
steroidogenesis.... You need to learn the boisynth path for these.... (on handout)you need to be able to draw all of the structures, and enzyme names, and patheways. you have to know everything on the sheet.... The parent of all of them is cholesterol. Part of it is chopped off and yo uare left with a ring structure with certain functional groups attached. If you count up thenumber of carbons in all of them, the first three are all 21 C steroids, the last 2 have 19, and then 18. Those are the natural versions, and they synthetic/man-made have different numbers. But you can count the number of carbons in the naturals to tell what the bioacti will be.
What is made hs to do with what enzymes are expressed in any particular cell, and no cells make every single steroid. If something goes wrong in the pathway, that influences other things being made in the pathway.
The way the handout works is it starts with cholesterol (you can look at another handout of cholsterol with a nomenclature of steroicogenic enzymes), and it shows the first structure of the pathway (prenenolone vs cholesterol, the side chanin is cleaved from pregnenolone to make cholesterol). You will want to mem prenenolone, and then memorize the numbering system fof the carbons. if you mem that scheme and then you learn the anems of the enzymes, you can figure out what the next structure cdown the line will look like. if you don't do that and you just go for mem them, you will probably drive yousrlf nuts. they loook too similar to each other.
the second part of the second sheet, gives all the enzymes with multiple names shown. We are going to use the 'trivial names' because they tell what it is actually doing. 17-alpha-hydroxylase; 17, 20 lyase: that tells exactly what it does... adds an OH at 17, and cleaves between 17 and 20.
There are 5 classes of steroid molecules:
Progestins
glucocorticoids
mineralocorticoids
androgens
estrogens
You want to look at the chart and id stuff you already know. At the lower left are mineralocorts ( lower left three)(aldosterone, corticosterone, and beta deoxycortosterone). next to that is glucocorticoid (2), the theird column (all ) is androgens. and the three to the far right are estrogens.
the way the enzymes work is tricky. the enzyme arrows point to what it catalyzes. If it doesn't go all the way across, then it doesn't make that item.
dezmolase is called 'side chain cleavage enzyme', 3 beta...(directly bleow it) goes by the name 3 beta hydroxy steroid dehydrogenase (3besta-hsd). it acts on carbon 3 to an OH, and something else.
and the lowest left enzyme is called aldosterone synthase (makes aldosterone).
The four major steroidogenic tissues testes, ovaries, adrenal cortex, and placenta.
You will run into 'peripheral conversion of steroids', means that step doesn't take place in a traditional steroidogenic tissue (like maybe body fat instead).
Let's talk about where they get cholesterol from, and what is the rate limiting step:
Cholesterol sources: some steroidogenic cells synth it from scratch from acetate. Most of the time, most of the cholesterol comes from the blood in the form of LDL (low density lypoproteins) they take them up, and use the cholesterol that is part of the LDL. uptaek is a place that steroidogenesis can be regulated. sites of steroid synth iwithin a cell... in either the mitochonodria, or in smooth ER. the cholesterol, and all of the subsequent molecules are shuttled between them. Smooth ER is called that because it doesn't lots of ribosomes attached. Ribosomes aren't needed for steroid synth. Steroids are not stored inside the cell. Cholesterol is processed through the pathway, it is highly lipid soluble, and goes right out of the cells. There are no vessicle storage of steroids. there is no way to regulate its release once it is made. If we look at the rate limiting step in the pathway, it is right at the beginning... it is the cleavage of the side-chain from cholesterol. It turns out that side-chain cleavage enzyme is in the inner mitochondrial membrane, and getting cholesterol to the inner mit mem is what makes it the rate limiting step. There is a protein repsonsible (StAR): steroidogenic acute regulatory protein, and it somehow fascilitates shuddling of cholesterol between the inner and outer mit mems. People with a mutation in StAR form little or no steroids. All of the regulatory pathways taht we are going to talk about, all of them act on StAR, as well as all the other enzymes in the pathway.
Last part of the general stuff: mech of steroid action... (handout in class)
Nuclear hormone receptor family... steroid receptors are part of that family. they jhave a hormoen binding domain and a DNA binding domain. thyroid hormones work differently than the steroids do. the thyroid response cell works in a dimer, binds, corepresors replaced by coacts. this is different. the basic concept is at the tope of the sheet.... read sheet. (fig 3-8 from je friffin and SR ojeda) availabel on eres) and fig 3-11 JE Griffin and SR Ojeda.
This is true for all of the molecules on the big pathway for steroids. there are distinct receptors for everything, but with some overlap between mineralocorts, and glucocorticoid receptors.
Adrenal cortex:
looks like a piramid with the inner part being the medulla. there are layers around the medulla (3 layers). the outer layer is called the zona-glomerulosa produces aldosterone; middle layer is called zona-fasiculata; innermost layer is zona-reticularis, both of which produce glucocortocoids and androgens. An easy way to remmber this as GFR from the outside in. (same acronym as from kidneys)
the ZGA layer is the only one that expresses aldosterone synthase. the products of the inner 2 are: androgens: androstenedioe, and DHEA (both are considered 'weak' androgens' which means they ahve relativly low affinity for receptors, not much testosterone or dihydortestosterone, and extermely little estrogens); and specific glucocorticoids: cortisol and corticosterone, these 2 are the most important in humans.
Glucocorticoids: (hypothalamic-pit-adreanl axis handout)...CRH: cortico releaseing hormone if there is no CRH then the pathway shuts down.
A stressor activiates this pathway.
Monday, April 30, 2007
Mon, April 30, adrenal receptor subtypes...
Today: Epi and Norepi.... we are basically one day behind, but we will get caught up by the end of the quarter.
Brief overview of sympathetic:
The hormones we are interested in are Ep and Norepi. if you are looking at a target cell somewhere in the body, have 2 sources that they can get Epi or Norepi from. 1) post-ganglionic neurons sympathetic neurons... realse Norepi as neurotransmitter 2) adrenal medulla (central part of the adrenal gland). AM releases both Epi and Norepi as hormones.
The sympathetic nervous system is part of the autonomic NS. The autonomic NS regulates endocrin and exocrin glands, contraction of smooth muscle, and cardiac muscle.
Autonomic neurons carry signals from the CNS out to the gland. There are 2 branches: parasympathic NS, and sympathetic NS. (you can disregard parasymp for this class). Sympathetic NS anatomy:
Post-ganglionic sympathetic fiber:
if we have a cell body of a neuron in the CNS, in the spinal cord (in this exp), an axon is sent out and is passed onto smooth or cardiac muscle, or endo/exo glands. The mid point between is a ganglion. it consists of lots of cell bodies and synapses. They are a grey whitish blob. It consists of thousands of axons synapsing on cell bodies. The one between CNS and the ganglion is called a pre0ganglionic fiber or neuron. between the ganglion and the endpoint is post-ganglionic fiber (neuron). At the axon terminal they release Norepi. And the NE reacts with the cells that are close to where it is released. It will either act right there, or go into the blood. This is one source of NE for these 4 targets.
the second source is the adrenal medulla:
The AM is really a highly modified post-symp ganglionic fiber. In the diagram for an AM:
starts with cell body in the spinal cord, and the pre-ganglionic fibers head towards the adrenal gland, and the pregang fiber has lots of axon terms, which make contact with cells, and these cells are called chromoffin cells, which are the source of the Epi/Norepi. Most of the Chromoffin cells release predominants Epi, and some release both Epi/Norepi. The cells release Epi/Norepi and the Epi/Norepi diffuse into the capillaries right next to the chromoffin cells. The part where the cells meet the caps, is all the adrenal medula. The AM is a 'sac' made of a group of cells, innervated by the pre-gang symp fibers. And when the PGSF fire they trigger the release of epi/ne.
IMportant points:
once the AM, when it rleases epi/ne, it is completely random where the epi/ne ends up.
when sympathetic neurons fire, THAT firing is highly directed.
The ratio of epi/norepi from AM, in humans, 80% epi, 20%ne. they also release some dopamine, but we aren't going to worry about that. Most of the hormone in the blood epi/ne, is epi. if it is being stim'd by epi comes from AM, norepi most likely it came from a post-gang symp fiber, even though a small amount comes from AM.
Now lets look at what the hormones look like. The diagram is on eres. tyrosine, dopa, dopamine, nor, epi.
this shows the biosynth pathways for these hormones. E, NE, and DA (dopamine) are all considered catecholamines. This refers to a certain structure of 2 hydroxyl groups off a aramatic ring, side by side (OH) then that is a catechol.
Tyrosine hydrosylase with tyrosine becaome dopa, and reacts with AA decarboxylase to become DA, and reacts with dopamine B-hydroxylase to make Nori, and cortisol triggers pheynylethanolamine-N-methyltranferase (PNMT) to make epi.
You really must know that.
The rate limiting step is the tyrosine hydroxylase step. Takes place in the chromoffin cells or in the post-gang.
Cortisol is produces in the cortex around the AM. Cortisol goes into the medula before it exits into the blood. And Cortisol stims the AM. If we look at the inputs that stimulate this pathway, regulation of Epi and NE secretion:
major regulator is the symp NS. it is always 'on' to a basal level. If the activity is activated beyond the basal level then it raises levels even more. Activation of symp NS is by flight or fight situations. other sits: during exercise, hypoglycemia, hypotension (low BP), and cold exposure. Some inputs trigger AM, and some trigger the PS/symp/NS. so leave yourselves open where it is not black or white. it is case dependant.
let's look at the receptors. 'adrenergic receptor subtypes' from eres:
Adrenergic receptors are the receptors for epi/norepil, do not call them epi-receptors.
The receptors are different in the G protein, and all have specific affinities. they have rougly similar afffinites for e/ne. since the receptors are all connected, but trigger different systems, so it is dependent upon which receptors are present in that area.
let's go on to look at the bioactivities...
the bio act. of e/ne have different catagories:
intermediary metabolism, cardiovascular system,, secretion of other hormones, arousal, metabolic rate.
Let's start with Int Met:
The effect of ep/norepi are mediated largely by beta-type adrenergic receptors. They increase the breakdown of fats and carbs into forms that can be used as fuel. The specific funtions are divided into different tissue types:
liver: (controls alot of int met): Epi/NE increase glycogenolosis (glsyogen breakdown), and increase gluconeogensis, and both of those act to increase blood glucose concentration.
muscle (skeletal): (a huge percentage of body weight): increase glycogenolosys, but the glucose that is freed up can't be released from the muscle because is it phos'd. that increases muscle glucose concetration to serve as fuel for the muscle, and enters glycolosys. it increases lactate and pyruvate production, which can leave the muscle and enter the circulation, and become substrates in the liver for making more glucose.
adapose tissue (fat):(less but still high majority):E/NE increase lipolysis (triglyceride is hydrolyzed to glycerol + fatty acids), and the glycerol is a substate for gluconeogenesis in the liver. the fatty acids can be used for fuel in cells outside the CNS, and alos be broken down into ketones to be used as fuel anyplace.
keypoints: actions on muscle and liver increase glucose concetration (and fat provides glycerol for gluconeogenesis), and fatty acids to allow for alternate fuels. (gluconeogenesis, only in liver or kidney).
Last part of this: in terms of protein met: epi/ne inhibit proteolysis. This is important later because it counteracts effects of cortisol. It is important to protect proteins to maintain structural integrity.
The big difffere3nce here between GH and epi are:
GH inhibits proteolysis, but GH stims aa uptake, but epi doesn't. epi just protects again proteolysis. epi does not act against glucose use in cells. it doesn't inhibit glucose uptake in cells, and doesn't counteract the uptake of insulin in cells like GH.
Let's move on to cardiovascular system:
effects on heart, blood vessels:
heart: mediated via beta 1 adrenergic receptors, what epi does: increases heart rate and contractility (force of contraction, larger means more blood pumped). the net result of both of these is they together increase cardiac output (volume of blood pumped by one ventricle per minute). Cardiac output is one of the things that determines how high blood pressure is.
Blood vessel adrenergic receptors:
-alpha Adrenergic recptors are in the smooth muscles that make upthe walls of blood vessels. Only alpha, then when they bind it causes the smooth muslces contract, and vessel diameter decreases (vasoconstriction)
-beta2 adr. recptors have the opposite effect: smooth muscle relaxes (vasodilation) and opens up blood vessels.
The effect on a blood vessel depends upon the concentrations of both of these. Most contain more alpha than beta adrenergic receptors. The response is vasoconstriction. the exceptions to this are: blood vessels in skeletal muscle, heart, liver, these contain more beta 2 than alpha, and so when epi/ne at high concetrations it causes vasodilation.
The interaction between going on from changing cardiac output vs changing blood vessel diameter. Heart to arteries to arterioles and returning capillaries, to veins and back to heart. (it is alphabetical) BP is measured in arteries. that pressure drives blood all the way through the cardiovascular system. it enters the arts and is at very high pressure, adn it flows down the pressure gradient. the only way for it to work properly is if arterial pressure is higher than veinous pressure, othewise it would go backwards. the body very closesly mointors and regs the pressure in arteries to keep it at the appropriate prssure. if it s too high then arteries in the brain will explode and you have a stroke and die. the two major things that determine blood pressure are: blood pressure entering arteries and blood pressure leaving the arteries. Blood in minus blood out, give you the blood pressure. you can increase the pressure in the arteries by: 1) increasing bloodflow into the arts,from the heart, (cardiac output) of 2) by decreasing the bloodflow out of the arts. what the sympathetic NS and epi/norepi do is to regulate cardiac output, and regulate bloodflow out of the arteries (decrease by vasoconstriction of blood flow out of arterioles. Vasoconstriction by raising E/NE binding to alpha-adrenergic cells.
Brief overview of sympathetic:
The hormones we are interested in are Ep and Norepi. if you are looking at a target cell somewhere in the body, have 2 sources that they can get Epi or Norepi from. 1) post-ganglionic neurons sympathetic neurons... realse Norepi as neurotransmitter 2) adrenal medulla (central part of the adrenal gland). AM releases both Epi and Norepi as hormones.
The sympathetic nervous system is part of the autonomic NS. The autonomic NS regulates endocrin and exocrin glands, contraction of smooth muscle, and cardiac muscle.
Autonomic neurons carry signals from the CNS out to the gland. There are 2 branches: parasympathic NS, and sympathetic NS. (you can disregard parasymp for this class). Sympathetic NS anatomy:
Post-ganglionic sympathetic fiber:
if we have a cell body of a neuron in the CNS, in the spinal cord (in this exp), an axon is sent out and is passed onto smooth or cardiac muscle, or endo/exo glands. The mid point between is a ganglion. it consists of lots of cell bodies and synapses. They are a grey whitish blob. It consists of thousands of axons synapsing on cell bodies. The one between CNS and the ganglion is called a pre0ganglionic fiber or neuron. between the ganglion and the endpoint is post-ganglionic fiber (neuron). At the axon terminal they release Norepi. And the NE reacts with the cells that are close to where it is released. It will either act right there, or go into the blood. This is one source of NE for these 4 targets.
the second source is the adrenal medulla:
The AM is really a highly modified post-symp ganglionic fiber. In the diagram for an AM:
starts with cell body in the spinal cord, and the pre-ganglionic fibers head towards the adrenal gland, and the pregang fiber has lots of axon terms, which make contact with cells, and these cells are called chromoffin cells, which are the source of the Epi/Norepi. Most of the Chromoffin cells release predominants Epi, and some release both Epi/Norepi. The cells release Epi/Norepi and the Epi/Norepi diffuse into the capillaries right next to the chromoffin cells. The part where the cells meet the caps, is all the adrenal medula. The AM is a 'sac' made of a group of cells, innervated by the pre-gang symp fibers. And when the PGSF fire they trigger the release of epi/ne.
IMportant points:
once the AM, when it rleases epi/ne, it is completely random where the epi/ne ends up.
when sympathetic neurons fire, THAT firing is highly directed.
The ratio of epi/norepi from AM, in humans, 80% epi, 20%ne. they also release some dopamine, but we aren't going to worry about that. Most of the hormone in the blood epi/ne, is epi. if it is being stim'd by epi comes from AM, norepi most likely it came from a post-gang symp fiber, even though a small amount comes from AM.
Now lets look at what the hormones look like. The diagram is on eres. tyrosine, dopa, dopamine, nor, epi.
this shows the biosynth pathways for these hormones. E, NE, and DA (dopamine) are all considered catecholamines. This refers to a certain structure of 2 hydroxyl groups off a aramatic ring, side by side (OH) then that is a catechol.
Tyrosine hydrosylase with tyrosine becaome dopa, and reacts with AA decarboxylase to become DA, and reacts with dopamine B-hydroxylase to make Nori, and cortisol triggers pheynylethanolamine-N-methyltranferase (PNMT) to make epi.
You really must know that.
The rate limiting step is the tyrosine hydroxylase step. Takes place in the chromoffin cells or in the post-gang.
Cortisol is produces in the cortex around the AM. Cortisol goes into the medula before it exits into the blood. And Cortisol stims the AM. If we look at the inputs that stimulate this pathway, regulation of Epi and NE secretion:
major regulator is the symp NS. it is always 'on' to a basal level. If the activity is activated beyond the basal level then it raises levels even more. Activation of symp NS is by flight or fight situations. other sits: during exercise, hypoglycemia, hypotension (low BP), and cold exposure. Some inputs trigger AM, and some trigger the PS/symp/NS. so leave yourselves open where it is not black or white. it is case dependant.
let's look at the receptors. 'adrenergic receptor subtypes' from eres:
Adrenergic receptors are the receptors for epi/norepil, do not call them epi-receptors.
The receptors are different in the G protein, and all have specific affinities. they have rougly similar afffinites for e/ne. since the receptors are all connected, but trigger different systems, so it is dependent upon which receptors are present in that area.
let's go on to look at the bioactivities...
the bio act. of e/ne have different catagories:
intermediary metabolism, cardiovascular system,, secretion of other hormones, arousal, metabolic rate.
Let's start with Int Met:
The effect of ep/norepi are mediated largely by beta-type adrenergic receptors. They increase the breakdown of fats and carbs into forms that can be used as fuel. The specific funtions are divided into different tissue types:
liver: (controls alot of int met): Epi/NE increase glycogenolosis (glsyogen breakdown), and increase gluconeogensis, and both of those act to increase blood glucose concentration.
muscle (skeletal): (a huge percentage of body weight): increase glycogenolosys, but the glucose that is freed up can't be released from the muscle because is it phos'd. that increases muscle glucose concetration to serve as fuel for the muscle, and enters glycolosys. it increases lactate and pyruvate production, which can leave the muscle and enter the circulation, and become substrates in the liver for making more glucose.
adapose tissue (fat):(less but still high majority):E/NE increase lipolysis (triglyceride is hydrolyzed to glycerol + fatty acids), and the glycerol is a substate for gluconeogenesis in the liver. the fatty acids can be used for fuel in cells outside the CNS, and alos be broken down into ketones to be used as fuel anyplace.
keypoints: actions on muscle and liver increase glucose concetration (and fat provides glycerol for gluconeogenesis), and fatty acids to allow for alternate fuels. (gluconeogenesis, only in liver or kidney).
Last part of this: in terms of protein met: epi/ne inhibit proteolysis. This is important later because it counteracts effects of cortisol. It is important to protect proteins to maintain structural integrity.
The big difffere3nce here between GH and epi are:
GH inhibits proteolysis, but GH stims aa uptake, but epi doesn't. epi just protects again proteolysis. epi does not act against glucose use in cells. it doesn't inhibit glucose uptake in cells, and doesn't counteract the uptake of insulin in cells like GH.
Let's move on to cardiovascular system:
effects on heart, blood vessels:
heart: mediated via beta 1 adrenergic receptors, what epi does: increases heart rate and contractility (force of contraction, larger means more blood pumped). the net result of both of these is they together increase cardiac output (volume of blood pumped by one ventricle per minute). Cardiac output is one of the things that determines how high blood pressure is.
Blood vessel adrenergic receptors:
-alpha Adrenergic recptors are in the smooth muscles that make upthe walls of blood vessels. Only alpha, then when they bind it causes the smooth muslces contract, and vessel diameter decreases (vasoconstriction)
-beta2 adr. recptors have the opposite effect: smooth muscle relaxes (vasodilation) and opens up blood vessels.
The effect on a blood vessel depends upon the concentrations of both of these. Most contain more alpha than beta adrenergic receptors. The response is vasoconstriction. the exceptions to this are: blood vessels in skeletal muscle, heart, liver, these contain more beta 2 than alpha, and so when epi/ne at high concetrations it causes vasodilation.
The interaction between going on from changing cardiac output vs changing blood vessel diameter. Heart to arteries to arterioles and returning capillaries, to veins and back to heart. (it is alphabetical) BP is measured in arteries. that pressure drives blood all the way through the cardiovascular system. it enters the arts and is at very high pressure, adn it flows down the pressure gradient. the only way for it to work properly is if arterial pressure is higher than veinous pressure, othewise it would go backwards. the body very closesly mointors and regs the pressure in arteries to keep it at the appropriate prssure. if it s too high then arteries in the brain will explode and you have a stroke and die. the two major things that determine blood pressure are: blood pressure entering arteries and blood pressure leaving the arteries. Blood in minus blood out, give you the blood pressure. you can increase the pressure in the arteries by: 1) increasing bloodflow into the arts,from the heart, (cardiac output) of 2) by decreasing the bloodflow out of the arts. what the sympathetic NS and epi/norepi do is to regulate cardiac output, and regulate bloodflow out of the arteries (decrease by vasoconstriction of blood flow out of arterioles. Vasoconstriction by raising E/NE binding to alpha-adrenergic cells.
Wednesday, April 25, 2007
wed, april 25
regulation of GH secreion: sim GH scc: GH affects metabolic pathways ... lobical that met factors ontreol GH
raised blood glucose stops secretion of GH and low blood gujlcoe raises SCC GH (short term/hours)
prolonged caloric deprivcation leads to raised GH (long term) probelmm that perons nom consuming sufficient protien rather than lower blood glucose levels (bf)
raised plasma AA (esp arginie) raises GH
acure stress raises GH (raised GH leads to raised glucose, and free fatty acid)
sleep leads to raised GH (GH has diuranl rhythm) inc sev hours after sleep
inhibition of GH:
low Th/hypotheyr.
raised corisol (classic strss hormoen) leads over time to raised cort low GH.
Emotional dep (bad emotional event)
Patterns of GH over life....
low from birth to childhood... goes up slightly in childhood and plattues until puberty.... spikes during puberty... and drops down to adulthood... and stays relatively stable after that....
GH no sig in prenatal growth (IGFs do
a+ at puberty, raises test and estrogens leads to GH secretion
estrgen acts directly on bone and everntually causes closeure of epiphyseal plate (cartilage)
in males, testo is converte to estrogen (closure)
test also acts dire on bone and dr stims growth (osteoblast activity)
estrogens alos stim bone growth
as people age greater than 60-70- GH declines and change in body comp lower muscle mass and raise percent fat.
disorders of GH secretion:
1) dwarfism - too little GH as a child
2) gigantism or giantism - too much
GH as a child
3) acromegaly - too much GH as an adult (pit tumor or hypoth. issue): increase in bone width, continued growth of cartilage, continued growth of soft tissues (liver, heart, tongue, kidneys), and tendency towards long standing hyperglycemia (diabetic over time)
Growth hormone mech of action...
this is the same for othes in the growth homrone family (prolactin)
one GH moelcue binds to two GH-R
JAK2 (just another kinase) is rebuited from the cytosol
JAK2 ginds to the GHR dimer and autophosphorylates on tyrosine residues (Y) (JAK2 is a tyrosine kinase)
JAK2 ph's the GHRs.
STATS (signal transducers and activators of transcription) bind to phos'd GHRs and are phos'd.
Two phos'd STATs are released into the cytoplasm and form a dimer and the dimer acts as a transcription factor to control gene expression.
(nothing to do with G protiens, no cAMP, etc)
GH circulates bound to a binding protein: extracellular doman of GH-R (aka GHR here )....
some GHR in liverare hydrolyzed and the extracellular domain leaves the plams membrane and is them GH-BP.
exam covers to here.....
Adrenal gland (medulla releases epi (E) and norepi (NE), is in the middle)(cortex surrounds medulla and releases steroid hormones)
E/NE are high in fight or flight sits. Cause heart rate to skyrocket during near miss.
they are secreted in response to stress.
but have other functions such as: regulate intermediary metabolism, regulate cardiovascular system, regulate secretion of other hormones.
raised blood glucose stops secretion of GH and low blood gujlcoe raises SCC GH (short term/hours)
prolonged caloric deprivcation leads to raised GH (long term) probelmm that perons nom consuming sufficient protien rather than lower blood glucose levels (bf)
raised plasma AA (esp arginie) raises GH
acure stress raises GH (raised GH leads to raised glucose, and free fatty acid)
sleep leads to raised GH (GH has diuranl rhythm) inc sev hours after sleep
inhibition of GH:
low Th/hypotheyr.
raised corisol (classic strss hormoen) leads over time to raised cort low GH.
Emotional dep (bad emotional event)
Patterns of GH over life....
low from birth to childhood... goes up slightly in childhood and plattues until puberty.... spikes during puberty... and drops down to adulthood... and stays relatively stable after that....
GH no sig in prenatal growth (IGFs do
a+ at puberty, raises test and estrogens leads to GH secretion
estrgen acts directly on bone and everntually causes closeure of epiphyseal plate (cartilage)
in males, testo is converte to estrogen (closure)
test also acts dire on bone and dr stims growth (osteoblast activity)
estrogens alos stim bone growth
as people age greater than 60-70- GH declines and change in body comp lower muscle mass and raise percent fat.
disorders of GH secretion:
1) dwarfism - too little GH as a child
2) gigantism or giantism - too much
GH as a child
3) acromegaly - too much GH as an adult (pit tumor or hypoth. issue): increase in bone width, continued growth of cartilage, continued growth of soft tissues (liver, heart, tongue, kidneys), and tendency towards long standing hyperglycemia (diabetic over time)
Growth hormone mech of action...
this is the same for othes in the growth homrone family (prolactin)
one GH moelcue binds to two GH-R
JAK2 (just another kinase) is rebuited from the cytosol
JAK2 ginds to the GHR dimer and autophosphorylates on tyrosine residues (Y) (JAK2 is a tyrosine kinase)
JAK2 ph's the GHRs.
STATS (signal transducers and activators of transcription) bind to phos'd GHRs and are phos'd.
Two phos'd STATs are released into the cytoplasm and form a dimer and the dimer acts as a transcription factor to control gene expression.
(nothing to do with G protiens, no cAMP, etc)
GH circulates bound to a binding protein: extracellular doman of GH-R (aka GHR here )....
some GHR in liverare hydrolyzed and the extracellular domain leaves the plams membrane and is them GH-BP.
exam covers to here.....
Adrenal gland (medulla releases epi (E) and norepi (NE), is in the middle)(cortex surrounds medulla and releases steroid hormones)
E/NE are high in fight or flight sits. Cause heart rate to skyrocket during near miss.
they are secreted in response to stress.
but have other functions such as: regulate intermediary metabolism, regulate cardiovascular system, regulate secretion of other hormones.
Monday, April 23, 2007
april 23 how bones grow....
Bone: osteoid (collagen and other proteins)
hydorxyabpatite crystals (CaPo4) are the crystals found in bones.
If you look at the cross section of bone, the head part is the epiphysis, and the narrow part is the diaphysis, and is divided by the epiphsyeal plate (made of cartilage: collage and polysacarides) In order for bone to grow the cartilage plate expands (gets thicker), and as the epiphaseal plate thickens it pushes the head of the bone moves upward, and the cartilage is replaced by bone. Without the epiphyseal plate, you can't get growth. This method means that the bones get longer at each end. (only in long bones that have the epiphyseal plate) (bones in the skull grow by a different method)
The last thing you need to know before we look at this in more detail...
the cell types for making bone: osteoblasts, secrete osteoid (proteins) and enzymes that increase precipitation of calcium. (ca2+ to form CaPO4)
and osteoclasts are involved in bone RESORBTION, they produce enzymes that dissolve bone, and clean things up. They are developmentally related to macrophages.
and for making cartilage: chondrocytes, secrete collage, and polysacarides together make cart.
At the bottom part of the bone figr 18.16, you need to add a layer of cells that is below and immediately below the epiphysis is the progenitor chondocytes. They give rise to chondrocytes. They are stimulated to differentiate into chondrocytes. then the chondrocytes proliferate and each gets bigger and bigger. The secrete and lay down cartilage in this process. They organize themselves into columns in the direction of bone growth. Once th echondrocytes are mature, they stop growing and are totally surrounded by the cartilage, and the nutriants can't get through, and their lifespan is limited. When the chondrocytes start to die the osteoclasts clean up the mess and are replaced with osteoBLASTS, and they lay down new bone. This process continues in cycle so that the end of the bone gets pushed farther and farther from the diaphysis. each cartilage plate can only make a certain amount of chondrocytes, and then the cartilage is all replaced with bone, and growth stops. (regulated by sex hormones)
Calcified cartilage is not yet bone, but it is a step in the bone growth, by it being digested by the osteoCLASTS, and osteoBLASTS come in to replace with bone. The chondrocytes have to be in columns or growth won't happen efficiently.
GROWTH HORMONE:
stimulates differentiation of progenitor chondrocytes to chondrocytes and it stimulates proliferation of chondrocytes, and it stimulates proliferation and activity of osteoBLASTS. You need both hormones to do the job: IGF-1 raise ccchondrocyte prliferation and hypertrophy (enlarge). also raises osteoblast proliferation and activity. if a person is missing either, then long bone growth doesn't occur at the normal rate (greatly diminished). (IGF-1 is locally produced dependant upon the presence of GH (growth hormone) (IGF-1: insuline growth factor 1)
hypothyroid means that you don't grow, it has a direct effect on bone.
T3, T4: increase GH secretion, and increase GH receptor expression, and raise proliferation and hypertrophy of chondrocytes, and they are needed for normal columnar organization of the chondrocytes in the epiphyseal cartilage.
At puberty the epiphyseal plate disappears and growth stops. they think it is due the the activation of estrogens. (the epiphyseal plate 'closes', which means the cartilage is gone) It is due to loss of stem cells that give rise to chondrocytes and this process is accelerated by estrogens.
andgrogens in men are converted to estrogens and does the same thing. without andgrogen/estrogen receptors then the people get very tall, because it takes so much longer for the process to happen.
GH, IGF1, also increase bone width by increasing the activity of osteoblasts which lay down new bone around the sides of the bone... this continues after puberty.
The effects on intermediary metabolism. We won't worry about IGFs in terms of the intermediary tmetabolism. (sometimes they are opposite too, so it is super confusing, just forget about it in regards to int. met) just pay attention to the GH.
GH effect lipid/carbohydrate metabolism, protein metabolism, and ______ metabolism.
protein metabolism is relate to growth, by increasing protein synth, and aa uptake into cells, increases RNA synth, which goes along with protein synth, and inhibits proteolysis.
Lipid and carb metabolism:
the nervous sysstem requires glucose as its major energy. without it you go into coma. there are mechanisms to make sure it never gets to low. the approach that GH uses to control is that it regulates pathways and intermediate met that conserves protein. it provides through these actions, it provides fuels that can be used in place of AAs, because you don't want to process the AAs to make glucose. the major ways the body does that is by breaking down muscles through gluconeogenesis to get AAs into glucose. But that is bad. GH prevents this process. instead it raises blood glucose levels in a way that protects the proteins in the bodies, so that they don't get turned into glucose.
if we look first at lipid metabolism...GH increases lipolysis (triglycerides are hydrolized into fatty acids + glycerol). the fatty acids can be used as an energy source by cells outside the central nervous system. This spares glucose for use by the CNS. (muscles use the fatty acids INSTEAD of the glucose, so the glucose is left free for the CNS to use instead.
glycerol is a substrate for gluconeogenesis (glycerol can be turned into glucose).
carb metabolism: effects on carb met... GH decreases glucose uptake by cells outside of the CNS. decreases glucose use (decreases glycolosis). stimulates gluconeogenesis. all of these act to increase the glucose concentration of the blood. People discribe these effects as 'increasing insulin resistance'. you need to know that insulin does the exact opposite of what GH does. It acts to get glucose out of blood. (gluconeogenesis: making glucose from some other substrate... glycolosis backwards) If you have too much GH it takes FAR MORE insulin to lower the blood glucose levels.
You want proteins to be protected. They are inhibit from use of glucose with GH.
REGULATION OF GH SECRETION:
Look at handout for basic feedback loop.
There are to hypothalic:
GHRH and somatostatin.
GHRH is 44AAs.
somatostatin is 14 AAs.
They are both fairly short peptides. they are probably going to be secretes as proforms. they are made by different population in the hypoth. in terms of their mech of action. both types of recptors are serpatine. serpantine recpetors are coupled to G-proteins.
GHRH is coupled to G(sub S) (increases cAMP)
sinatistatin is coupled to G(sub i) (decrease cAMP)
as cAMP increase leads to calcium entry into the cell, and the increase in calcium(Ca2+) stimulates exocytosis of GH.
GHRH vs somatostatin are reciprocal. if you totally disconnect the pit from the hypth, the net action is a decrease in GH secretion.
GHRH is the more dominant/controlling factor. they both together regulate GH secretion.
At the bottom of the handout are other factors that regulate GH secretion.
Similar control as thyroid hormones.
Conditions that stim secretion:
hypglycemia, fasting; raise plasma AA (esp arg); prolonged caloric deprivation; acute stress; exercise; puberty (estrogens/androgens); sleep.
Conditions that inhibit secretion: hyperglycemia (raises fatty acids); hypthyroidism; aging; emotional deprivation; raised cortisol for extended period of time.
hydorxyabpatite crystals (CaPo4) are the crystals found in bones.
If you look at the cross section of bone, the head part is the epiphysis, and the narrow part is the diaphysis, and is divided by the epiphsyeal plate (made of cartilage: collage and polysacarides) In order for bone to grow the cartilage plate expands (gets thicker), and as the epiphaseal plate thickens it pushes the head of the bone moves upward, and the cartilage is replaced by bone. Without the epiphyseal plate, you can't get growth. This method means that the bones get longer at each end. (only in long bones that have the epiphyseal plate) (bones in the skull grow by a different method)
The last thing you need to know before we look at this in more detail...
the cell types for making bone: osteoblasts, secrete osteoid (proteins) and enzymes that increase precipitation of calcium. (ca2+ to form CaPO4)
and osteoclasts are involved in bone RESORBTION, they produce enzymes that dissolve bone, and clean things up. They are developmentally related to macrophages.
and for making cartilage: chondrocytes, secrete collage, and polysacarides together make cart.
At the bottom part of the bone figr 18.16, you need to add a layer of cells that is below and immediately below the epiphysis is the progenitor chondocytes. They give rise to chondrocytes. They are stimulated to differentiate into chondrocytes. then the chondrocytes proliferate and each gets bigger and bigger. The secrete and lay down cartilage in this process. They organize themselves into columns in the direction of bone growth. Once th echondrocytes are mature, they stop growing and are totally surrounded by the cartilage, and the nutriants can't get through, and their lifespan is limited. When the chondrocytes start to die the osteoclasts clean up the mess and are replaced with osteoBLASTS, and they lay down new bone. This process continues in cycle so that the end of the bone gets pushed farther and farther from the diaphysis. each cartilage plate can only make a certain amount of chondrocytes, and then the cartilage is all replaced with bone, and growth stops. (regulated by sex hormones)
Calcified cartilage is not yet bone, but it is a step in the bone growth, by it being digested by the osteoCLASTS, and osteoBLASTS come in to replace with bone. The chondrocytes have to be in columns or growth won't happen efficiently.
GROWTH HORMONE:
stimulates differentiation of progenitor chondrocytes to chondrocytes and it stimulates proliferation of chondrocytes, and it stimulates proliferation and activity of osteoBLASTS. You need both hormones to do the job: IGF-1 raise ccchondrocyte prliferation and hypertrophy (enlarge). also raises osteoblast proliferation and activity. if a person is missing either, then long bone growth doesn't occur at the normal rate (greatly diminished). (IGF-1 is locally produced dependant upon the presence of GH (growth hormone) (IGF-1: insuline growth factor 1)
hypothyroid means that you don't grow, it has a direct effect on bone.
T3, T4: increase GH secretion, and increase GH receptor expression, and raise proliferation and hypertrophy of chondrocytes, and they are needed for normal columnar organization of the chondrocytes in the epiphyseal cartilage.
At puberty the epiphyseal plate disappears and growth stops. they think it is due the the activation of estrogens. (the epiphyseal plate 'closes', which means the cartilage is gone) It is due to loss of stem cells that give rise to chondrocytes and this process is accelerated by estrogens.
andgrogens in men are converted to estrogens and does the same thing. without andgrogen/estrogen receptors then the people get very tall, because it takes so much longer for the process to happen.
GH, IGF1, also increase bone width by increasing the activity of osteoblasts which lay down new bone around the sides of the bone... this continues after puberty.
The effects on intermediary metabolism. We won't worry about IGFs in terms of the intermediary tmetabolism. (sometimes they are opposite too, so it is super confusing, just forget about it in regards to int. met) just pay attention to the GH.
GH effect lipid/carbohydrate metabolism, protein metabolism, and ______ metabolism.
protein metabolism is relate to growth, by increasing protein synth, and aa uptake into cells, increases RNA synth, which goes along with protein synth, and inhibits proteolysis.
Lipid and carb metabolism:
the nervous sysstem requires glucose as its major energy. without it you go into coma. there are mechanisms to make sure it never gets to low. the approach that GH uses to control is that it regulates pathways and intermediate met that conserves protein. it provides through these actions, it provides fuels that can be used in place of AAs, because you don't want to process the AAs to make glucose. the major ways the body does that is by breaking down muscles through gluconeogenesis to get AAs into glucose. But that is bad. GH prevents this process. instead it raises blood glucose levels in a way that protects the proteins in the bodies, so that they don't get turned into glucose.
if we look first at lipid metabolism...GH increases lipolysis (triglycerides are hydrolized into fatty acids + glycerol). the fatty acids can be used as an energy source by cells outside the central nervous system. This spares glucose for use by the CNS. (muscles use the fatty acids INSTEAD of the glucose, so the glucose is left free for the CNS to use instead.
glycerol is a substrate for gluconeogenesis (glycerol can be turned into glucose).
carb metabolism: effects on carb met... GH decreases glucose uptake by cells outside of the CNS. decreases glucose use (decreases glycolosis). stimulates gluconeogenesis. all of these act to increase the glucose concentration of the blood. People discribe these effects as 'increasing insulin resistance'. you need to know that insulin does the exact opposite of what GH does. It acts to get glucose out of blood. (gluconeogenesis: making glucose from some other substrate... glycolosis backwards) If you have too much GH it takes FAR MORE insulin to lower the blood glucose levels.
You want proteins to be protected. They are inhibit from use of glucose with GH.
REGULATION OF GH SECRETION:
Look at handout for basic feedback loop.
There are to hypothalic:
GHRH and somatostatin.
GHRH is 44AAs.
somatostatin is 14 AAs.
They are both fairly short peptides. they are probably going to be secretes as proforms. they are made by different population in the hypoth. in terms of their mech of action. both types of recptors are serpatine. serpantine recpetors are coupled to G-proteins.
GHRH is coupled to G(sub S) (increases cAMP)
sinatistatin is coupled to G(sub i) (decrease cAMP)
as cAMP increase leads to calcium entry into the cell, and the increase in calcium(Ca2+) stimulates exocytosis of GH.
GHRH vs somatostatin are reciprocal. if you totally disconnect the pit from the hypth, the net action is a decrease in GH secretion.
GHRH is the more dominant/controlling factor. they both together regulate GH secretion.
At the bottom of the handout are other factors that regulate GH secretion.
Similar control as thyroid hormones.
Conditions that stim secretion:
hypglycemia, fasting; raise plasma AA (esp arg); prolonged caloric deprivation; acute stress; exercise; puberty (estrogens/androgens); sleep.
Conditions that inhibit secretion: hyperglycemia (raises fatty acids); hypthyroidism; aging; emotional deprivation; raised cortisol for extended period of time.
Friday, April 20, 2007
fri, april 20th.
hypothyroidism continued...
causes:
1) failure of thyroid gland to make enough TH (primary hypothyroidism is most common)
... in developing countries with insuff iodine hypothyroidism due to deficiency of iodine in diet. When iodine deficient you can't produce T3/T4, so loss of feedback control of TRH/TSH (negative feedback loop missing) which leads to increased secretion of TSH and thyroid gland grow to compensate. ( only sometimes do they get goiter). the thyroid gland is unusual in that it is able to store colloid. the thyroid evolved to protect individual where iodine is not plentiful. colloid can supply TH for weeks.
tx for hypothyroidism: thyroxine pills (T4) which is metabolically converted to T3, and over time would reinstate negative feedback look, and decrease TSH/TRH and hopefully decrease goiter. T4 suppliment because it has a much longer half life so it is easier to maintain steady levels with.
2) thyroid follicles are destroyed (hashimoto's disease): autoimmune disease .
the body can compensate by growing non-attacked follicles but eventually lose function.
tx-thyroxine
3)inactivation of TSH receptors: due to muation of inactiavtion by antibodies blocking receptors.
the thyroid gland is not stimulated to produce T3 and T4. Have raised TRH/TSH secretion but no enlargement of thyroid b/c receptor is inactive. only have growth of goiter if TSH receptoer is overactive.
second degree hypothyroidism: problem at hypothalamic or pit level.
1. decreased TRH secretion
and
2. decreased TSH secretion
both are much less common, and are potentially caused by tumor growth.
can determine if pit/hypoth cause of illness by measuring TSH levels in the blood if TSH is low that it is pit/hypoth NOT thyroid. if give bolus of TRH and TSH levels rise, then the issue is hypoth. if give bolus TRH and TSH still low, the its the pit.
Thyroid hormone resistant: TH made but cells not recognizing it.
1. loss of function mutation in 1+ TH receptor
2. loss of function mut in transporter in plasma membrane of target cells.
loss of TBG would decrease half life of TH but body would generally be able to compensate.
HYPERTHYROIDISM: cells recieve too much TH stimulation.
signs/symptoms: weight loss, feel warm/hot, jittery/nervous/anxious, rapid heart rate, muscle wasting (proteolysis>protein synth), weakness, fatigue, reproductive tract issue.
Causes:
1. tumors that secrete TRH/TSH/T3/T4 (rare)
2. injest thyroid supplements (sometimes for weight loss) (ie: exsessive use of kelp tabs)
3. Graves Disease (most common and tends in families): autoimmune disease that produces antibodies that activate the TSH receptors (antibodies = thyroid stimulating immunoglobulins TSIs)
TSH-R on thyr activated by TSI -> produces too much T3/T4 -> signals pit to reduce TSH production even though it is low already (negative feedback loop fails to mediate levels).
tx: initially attempt to limit T3/T4 production with TX, and next step is radioactive iodine which incorporates to colloid and helps to destroy thyroid gland. This makes the person hypothyroid, but that can be treated with TX (thyroxine).
The antibodies additionally tend to attack muscle tissue surrounding the eyes.
TSI can also cause goiter... goiter is not only a symptom of hypo/hyper thyroidism.
GROWTH HORMONE (see handout) (GH)
It is important because:
1) absolutely nec for post natal growth... no GH = stunted growth.
2) regulates a lot of metabolic pathways.
GHRH (Growth Hormone Releasing Hormone) + somatostatin control GH secretion.
... both act on ant.pit. (GHRH is positive control, and somatostatin is negative control) stimulates somatotropes.
1. GH binds target tissue and causes reaction
2. GH acts on liver and other tissues and stimulates them to produce insulin like growth factor (IGF1) .... binds target tissue and cause reaction.
>> both 1 and 2 needed together to cause the effect.
Approach: structure GH, structure IGF, biological activities, reglulation/secretion, GH-R, pathologies.
GROWTH HORMONE STRUCTURE:
-non-glycosylated single chain polypeptide (191aa, mw=20K)
-structurally, aa seq conserved between GH and prolactin
... structural similarity extends to placental lactogens as well.
......similarity makes them 'family':: GH-PRL-PL gene hormone family
-important of structural similarity>> get lot of info about mech action within family because mech of action is much the same.
-GH=large protein>> unusual binding (~40%) circulates bound to GH-BP in the blood
Half-life is roughly 30 mins (but that half life is increase by being bound to the BP.
INSULIN-LIKE-GROWTH-FACTORS
two types: IGF1 and IGF2 (or IGF-II)
IGF1 - major part of regulation via GH but not all regulation is by GH
IGF2 - regulated by lots of things
.. single chain polypeptide (mw ~ 7K)
.. circulates bound to BP
.. structure is similar to insulin
.. most IGF1 in the blood is from liver under regulation by GH, but IGF1 is also made in numerous other target tissues, and those are also regulated by GH, and others.
When IGF-1 is made in other tissues, they mostly act in situ, although some will get into circulation (autocrine/paracrine effect)
Somatomedan hypothesis: GH effects to raise IGF1 production by the liver and IGF1 then mediates ALL actions of GH (but that is a far oversimplification)
Current view (much more like handout): GH effects to raise IGF1 secretion in many tissues, and some systems require both GH & IGF1 to get biological effect.
In other systems GH can act independantly of IGF1 but you must look at specific systems to see that.
causes:
1) failure of thyroid gland to make enough TH (primary hypothyroidism is most common)
... in developing countries with insuff iodine hypothyroidism due to deficiency of iodine in diet. When iodine deficient you can't produce T3/T4, so loss of feedback control of TRH/TSH (negative feedback loop missing) which leads to increased secretion of TSH and thyroid gland grow to compensate. ( only sometimes do they get goiter). the thyroid gland is unusual in that it is able to store colloid. the thyroid evolved to protect individual where iodine is not plentiful. colloid can supply TH for weeks.
tx for hypothyroidism: thyroxine pills (T4) which is metabolically converted to T3, and over time would reinstate negative feedback look, and decrease TSH/TRH and hopefully decrease goiter. T4 suppliment because it has a much longer half life so it is easier to maintain steady levels with.
2) thyroid follicles are destroyed (hashimoto's disease): autoimmune disease .
the body can compensate by growing non-attacked follicles but eventually lose function.
tx-thyroxine
3)inactivation of TSH receptors: due to muation of inactiavtion by antibodies blocking receptors.
the thyroid gland is not stimulated to produce T3 and T4. Have raised TRH/TSH secretion but no enlargement of thyroid b/c receptor is inactive. only have growth of goiter if TSH receptoer is overactive.
second degree hypothyroidism: problem at hypothalamic or pit level.
1. decreased TRH secretion
and
2. decreased TSH secretion
both are much less common, and are potentially caused by tumor growth.
can determine if pit/hypoth cause of illness by measuring TSH levels in the blood if TSH is low that it is pit/hypoth NOT thyroid. if give bolus of TRH and TSH levels rise, then the issue is hypoth. if give bolus TRH and TSH still low, the its the pit.
Thyroid hormone resistant: TH made but cells not recognizing it.
1. loss of function mutation in 1+ TH receptor
2. loss of function mut in transporter in plasma membrane of target cells.
loss of TBG would decrease half life of TH but body would generally be able to compensate.
HYPERTHYROIDISM: cells recieve too much TH stimulation.
signs/symptoms: weight loss, feel warm/hot, jittery/nervous/anxious, rapid heart rate, muscle wasting (proteolysis>protein synth), weakness, fatigue, reproductive tract issue.
Causes:
1. tumors that secrete TRH/TSH/T3/T4 (rare)
2. injest thyroid supplements (sometimes for weight loss) (ie: exsessive use of kelp tabs)
3. Graves Disease (most common and tends in families): autoimmune disease that produces antibodies that activate the TSH receptors (antibodies = thyroid stimulating immunoglobulins TSIs)
TSH-R on thyr activated by TSI -> produces too much T3/T4 -> signals pit to reduce TSH production even though it is low already (negative feedback loop fails to mediate levels).
tx: initially attempt to limit T3/T4 production with TX, and next step is radioactive iodine which incorporates to colloid and helps to destroy thyroid gland. This makes the person hypothyroid, but that can be treated with TX (thyroxine).
The antibodies additionally tend to attack muscle tissue surrounding the eyes.
TSI can also cause goiter... goiter is not only a symptom of hypo/hyper thyroidism.
GROWTH HORMONE (see handout) (GH)
It is important because:
1) absolutely nec for post natal growth... no GH = stunted growth.
2) regulates a lot of metabolic pathways.
GHRH (Growth Hormone Releasing Hormone) + somatostatin control GH secretion.
... both act on ant.pit. (GHRH is positive control, and somatostatin is negative control) stimulates somatotropes.
1. GH binds target tissue and causes reaction
2. GH acts on liver and other tissues and stimulates them to produce insulin like growth factor (IGF1) .... binds target tissue and cause reaction.
>> both 1 and 2 needed together to cause the effect.
Approach: structure GH, structure IGF, biological activities, reglulation/secretion, GH-R, pathologies.
GROWTH HORMONE STRUCTURE:
-non-glycosylated single chain polypeptide (191aa, mw=20K)
-structurally, aa seq conserved between GH and prolactin
... structural similarity extends to placental lactogens as well.
......similarity makes them 'family':: GH-PRL-PL gene hormone family
-important of structural similarity>> get lot of info about mech action within family because mech of action is much the same.
-GH=large protein>> unusual binding (~40%) circulates bound to GH-BP in the blood
Half-life is roughly 30 mins (but that half life is increase by being bound to the BP.
INSULIN-LIKE-GROWTH-FACTORS
two types: IGF1 and IGF2 (or IGF-II)
IGF1 - major part of regulation via GH but not all regulation is by GH
IGF2 - regulated by lots of things
.. single chain polypeptide (mw ~ 7K)
.. circulates bound to BP
.. structure is similar to insulin
.. most IGF1 in the blood is from liver under regulation by GH, but IGF1 is also made in numerous other target tissues, and those are also regulated by GH, and others.
When IGF-1 is made in other tissues, they mostly act in situ, although some will get into circulation (autocrine/paracrine effect)
Somatomedan hypothesis: GH effects to raise IGF1 production by the liver and IGF1 then mediates ALL actions of GH (but that is a far oversimplification)
Current view (much more like handout): GH effects to raise IGF1 secretion in many tissues, and some systems require both GH & IGF1 to get biological effect.
In other systems GH can act independantly of IGF1 but you must look at specific systems to see that.
Thursday, April 19, 2007
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)
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)
Subscribe to:
Posts (Atom)