Endocrine physiology: Hormone structure and fxn
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What are the 4 major classes of hormones?
- Peptide and protein hormones
- Steroid Hormones
- Vitamin derivatives
What are amines? Does it have a subgroup?
They are derivatives of tyrosine amino acid residues and are one of the major classes of hormones. They have 2 subgroups called Thyroid hormone and the catecolamines.
A subclass of amine- thyroid hormone which is hydrophobic bc of the benzene rings. They are made up by T4 and T3 thyroid hormone and the number of iodine is told by the number after T.
What causes the iodinization of the benzene ring?
It is synthesized by the thyroid follicular cells.
Peptide and protein hormones are usually?
What is the biggest class of hormones?
peptide/protein hormone class
How are the peptide/protein hormones made?
So in the DNA there are the noncoding regions, eons, introns and the wonderful poly-A. All of the exon regions are spliced and we get a pre-prohormone which is the NH3 signal-hormone and co-peptide. Then after further processing we get a pro hormone which is the hormone and the co-peptide together and finally we get the actual active hormone once the hormone and the co-peptide is cleaved from each other.
Does the co-peptide have an action?
It may or may not. I guess it depends.
What are the common peptide hormone families?
- Well we have the glycogen protein family which is made of alpha and beta heterodimers. The alpha is always the same but the beta is different allowing for there to be different hormones.
- The most common are: LH, FSH, TSH, hCG.
So pregnant women are known for their irritability (you remember mom), why?
well hCG is very high during pregnancy (hence pregnancy tests) and because hCG and TSH are so similar some hCG binds to the TSH receptors since there is some overlap of hormone binding for their corresponding GPCRs because the hormones usually work in different target tissues so since the hCG levels are so high, some hCG will bind to the TSH receptors.
What are some common pro-hormones and what do they have?
- POMC (propiomelanocortin)- ACTH
- Propressophysin- ADH
- Propthotropin releasing hormone- has TSH
Steroid hormones what are they and what are some examples?
Well they are one of the major types of hormones and their precursors are cholesterol so they are hydrophobic.
What are some examples of steroid hormones, the type and the synthesization?
- Cortisol- glucortoid synthesized by the adrenal cortex
- Aldosterone- mineralcortoid synthesized by the adrenal cortex
- testosterone- androgen made by the gonads
- progesterone - progestin made by the gonads
- estradiol- estrogen synthesized by the gonads
- 1,25 (OH2) cholecalciferol- calciferol
How are peptide and protein hormones stored and secreted?
Since they are hydrophilic they are stored in secretory ganules from the ER. They are released in exocytosis: when there is a stimulus, there is increased Ca +/- cAMP which makes for there to be exocytosis by microtubular and the microfilament system which acts as a road for the granules to come out via exocytosis and because it is hydrophilic they can circulate in the blood until they reach their receptor at the target tissue
How are thyroid hormones stored and secreted?
So this one is kinda interesting, as a pre-thyroid hormone it is hydrophilic but it is hydrophobic as the actual hormone. It is stored outside of the F cells as a colloid (which is an iodionated Tg). Following exocytosis and proteolysis it is released by simple diffusion.
What is Tg?
Tg is prethyroid hormone which provided the tyrosine residues for iodination in the benzene ring.
So how do we get T4 and T3?
- So Tg is iodinated by iodine and if it gets 1 iodine it is MIT but if it gets 2 then it is DIT.
- • DIT + MIT= T3
- • DIT+ DIT= T4
- • When needed they endocytose and then there is cleavage and then we get T3 and T4 and we get simple diffusion out.
How are steroid hormones stored and exocytosed?
stored in the form of lipid droplets and they are released by simple diffusion
What are the different type of endocrine gland stumuli and what do they act on?
- Humoral stimulus: When there is low Ca+ then the parathyroid gland detects it and there is secretion of PTH which acts to increase the blood Ca+
- Neural stimulus: Preganglionic sympathetic fibers stimulate the adrenal medulla to kick out catecholamines (norei and epi)
- Hormonal stimulus: Hypothalamus secretes hormones that stimulate the pituitary gland to secrete hormones that stimulate orher endocrine glands to secrete hormones.
What is constitutive secretion?
constitutive secretion doesn’t need to be regulated and therefore is unregulated membrane fusion because it is replacing the cell membrane proteins and this is carried out by transport vesicles.
What is regulated secretion?
There is regulated secretion which carries secretory proteins and this is regulated and this is carried out by secretory vesicles.
How are the hormones transported from A to target organs B?
- Catecholamine and peptides: Water soluble and most circulate unbound in plasma.
- * They have a short half life because they are unbound and expose themselves to be degraded
- Steroid and thyroid hormones: Lipid soluble, circulate in the plasma bound to carrier protein
- *They have longer half lives
How is there an equilibrium between free and bound hormones?
There is release of hormone from the endocrine cells and the majority of the hormone will be attached to the carrier bound hormone but there will be an equilibrium between the free hormone and the carrier bound hormone. This carrier bound protein will serve as a reservoir to prevent the hormone from being degraded but it will also restrict the free hormone to get access to the receptor since they are in the cell and only the free hormone can cross the cell surface to reach the intracellular receptor and have the biological effects but at the same time, the free hormone is much more at risk of hormone degradation.
What is peripheral transformation?
Hormone actually reaches the peripheral transformation which makes the hormone even more potent (like T4 once it reaches target tissue it becomes T3 and this is more potent)
rate of hormone removal is influenced by?
- Disease of liver and kidney
- Target tissues
What is the primary route of excretion of hormones?
Urine is the primary route of excretion od hormone degradation products
What determines the frequency of hormonal dosing?
- Circulating hormone half-life determines the frequency of dosing
- Example- If a patient doesn’t have enough thyroid hormone then we usually choose T4 and not T3 since: T4 has a half life of 7 days and therefore all we need to rx is a single dose but it does take about a month to reach a new steady state. T3 has a half life of 1 day and therefore we would need to rx the patient the med like 2-3 times a day.
How are hormones measured?
- Antibody capture: hormone onto an immobilized surface with a second antibody coupled to a chemiluminecsent or radioactive signals for detection
- Correct imterpretation in the clinical context: wide normal range depending on age and gender, pulsatile secretion (may want to do various), factors modulating secretion such as sleep, meals, and meds ect.
So how can we know where the receptors for various hormones are located?
- Hormones only interact with cells that have binding sites that are specific for the particular hormones.
- Lipid insoluble hormones have receptors at the surface of the plasma membrane.
- Lipid soluble hormones that can pass through the plasma membrane have intracellular receptors.
How do plasma membrane bound hormone receptors work?
After a hormone binds to the receptor, the receptor initiates events that lead to a response: Some receptots alter membrane permeability. Some receptros avctivate G proteins. Some receptors alter intracellular enzyme activity- Membrane receptors on the cell surface and they have different second messengers and that is what will result in different gene expression in the nucleus
Ion channel system
Hormone bind to receptor coupled with G-protein opens Ca channels and in this case the Ca is second messenger which will go on to bind calmodulin and go in with all of the metabolic pathway.
Adenyl Cyclase- cAMP system
Adynel-cyclase is a trimer (α,β, γ) and Gs is stimulation and Gi is inhibitory. If it is stimulated it increases (ie forms ) cAMP and if it is inhibitory it decrases cAMP (breaks it down)
cAMP activation of PKA
PKA is normally not functioning because there is a regulatory and a catalytic domain and the regulatory domain inhibits the catalytic. cAMP binds to the regulatory domain and separates it from the catalytic domain to allow for the catalytic domain to work and change the protein to alter it thereby altering its function and allowing for there to be biological effects.
Hormone couples with the receptor and the G protein and this works with the PLC which is made from PIP2 which then makes 2 second messengers DAG and IP3. DAG works with Protein Kinase C and IP3 works to increase the intracellular Ca+
RET Receptor Tyrosine Kinase
When we get a GDNF or another hormone to bind to the tyrosine kinase, if 2 of them are activated then they will join forming a dimer but at this time the tyrosine regions are activated yet the there is still no phosphoralyzation. ATP will be giving us the phosphorylation on the tyrosine. Then relay protein attaches to the phosphorylated tyrosine to signal different signaling responses. With this we can get many signaling responses
Receptors for thyroid and steroid hormones
Receptor is usually inside and it is usually transcription factors because they are going to the nucleus, binding to the DNA and depending on the different hormone, they bind to regulate gene expression.
What has to happen in order for the steroid hormone to go into the cell and what happens after that?
Steroid hormone will not be able to go into the cell until it has been released from the carrier protein. As a free hormone they will be able to go in and bind to the receptor either in the nucleus and then regulate the transcription of the target gene and have the biological effects
Feedback Regulation (H-P-X axis)
- •The gonads, thyroid and adrenal feedback to let the pituitary and hypothalamus that it has enough. Now inhibit the earlier hormones.
- •Negative feedback comprises various means of limiting the extent of a hormone’s action once it has accomplished its primary purpose. In systems with more than one hormone in series the final hormone’s actions include feedback inhibition of secretion of the earlier hormones
1ry hyperthyroidism means that dysfunction occurs at the level of the thyroid.
A patient presents with symptoms of hormone excess. What is the first thing I (you, we, you know what I mean) need to do and what are the possible causes?
- • If [H] level is increased
- – tumors,
- – diseases of liver or kidney,
- – defect in the enzyme converting the hormone of interest to another product
- • If [H] level is not increased
- – presence of stimulatory antibodies on hormone’s receptor
- – overexpression of other hormones
- – decrease of carrier protein,
- – constitutive activation of receptor or downstream signaling pathways
A patient presents with symptoms of hormone deficiency. What is the first thing I (you, we, you know what I mean) need to do and what are the possible causes?
- • If [H] level is decreased
- – defect in the endocrine gland secreting hormone of interest
- – defect in pituitary gland or hypothylamus
- • If [H] level is not decreased
- – presence of inhibitory antibodies to the receptor
- – presence of antagonist (drug),
- – hormone resistance due to mutation in receptor or downstream signaling pathways
So one hormone one receptor right? Why or why not?
Kinda but not really. a given hormone can have more than one receptor, each of which can have different affinities for the hormone and can activate different signaling pathways.
Hormones have only one action right? Why or why not?
• A hormone can have a variety of actions that occur over different time courses depending on variables such as whether the actions are via the highest affinity receptor versus another lower affinity receptor, or due to the primary versus secondary transcriptional responses, or due to more or less complex second messenger interactions in the signaling pathways
Describe a typical signaling pathway.
• A typical signaling pathway involves a hormone whose binding activates a receptor, which then activates a G protein which results in an increased level of second messengers which activate enzymes which phosphorylate or dephosphorylate other proteins that either serve as transcription factors or regulate other protein synthesis/activity.
So the if one cell has the same receptor as another cell then the effect will be the same. Yes or no and why?
• Different effects of second messengers occur in different cells even when they have the same receptors, due to the differences in transcription factors and enzymes that are present in one cell versus another
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