Hormone activity depends on the existence of hormone (hormone s concentration) and its receptor.
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1 Physiology 19 1 Revision Last lecture we were talking about types of hormones: 1-peptid: produced from hypothalamus or from anterior pituitary. 2- Amines (catecholamines (such as; epinephrine, norepinephrinen ), thyroxin). 3- Steroid: produced from adrenal cortex, corpus luteum, testes, ovaries, placenta, kidney (produces 1,25- Dihydroxycholecalciferol(calcitriol); the active vitamin D, when you will study the gastrointestinal track you will know that the vitamin D is in the skin through ultra-violet light then it goes to the liver, In the liver it is hydroxylated at position 25 to become 25 hydroxycholecalciferol then in the kidney it is hydroxylated at position 1) The action of hormones is not required we will take them next year, Thyroxin its action is to increase the receptors for adrenergic (norepinephrine and epinephrine) so it will increase the sensitivity to epinephrine one of the activities of epinephrine is to increase heart rate, thyroxin increases the metabolic rate so it increases the body temperature, and it increases protein synthesis. Should we have a stimulus to have an active hormone? Yes we should have a stimulus either a chemical, neural or hormonal. Example,insulin: if there is a high level of glucose it will stimulate the glucose receptors on the β cells of pancreas that will stimulate insulin. Hormone activity Hormone activity depends on the existence of hormone (hormone s concentration) and its receptor. Receptors are dynamic and constantly synthesized and broken down and decreased there are two things that affect the receptors: 1) Down-regulation: if the receptors are less, too much hormone will cause little action (it is also called desynthesization or resistance ) Why do we want to have down-regulation? If we have a hormone for long time and with high concentration then we will have a lot of action what to do?? We should decrease the number of receptors. If you decrease the number of receptors, it is like a negative feedback then you will decrease the activity of the hormone. How the receptors are decreased?? It is internalized; it gets into the cell so the receptor is no longer exposed to the hormone
2 Physiology 19 2 so they won t bind to each other. It is applied specially to the hormones that are water soluble like catecholamines. Down-regulation is important especially for those who are always stressed so large amount of epinephrine or norepinephrine for long time (a lot of sympathetic stimulation) so even if the concentration is high the end result is normal. For example: If we have a person with a lot of insulin, he will have also a lot of glucose hyperglycemia why??!! Because we have few insulin receptors due to down-regulation. 2) Up-regulation: the receptors increase in number so the little amount of hormone will have too much action, so the activity of the hormone is increased. Why do we want up-regulation? Up-regulation: Now if you have a dormant state where you don t have too much stimulation (rest state) the receptors will be externalized, so even that we have little amount of hormone there would be a huge action. "يصعب التفرقة بين األخذ والعطاء ألنهما يعطيان مدلوال واحدا في عالم الروح فكل مرة أعطيت لقد أخذت لست أعني أن أحدا قد أعطى لي شيئا إنما أعني أنني أخذت نفس الذي أعطيت ألن فرحتي بما أعطيت لم تكن أقل من فرحة الذين أخذوا" سيد قطب *Up-regulation and down-regulation are a kind of negative feedback (control of the hormone action on the cell). What might prevent the up-regulation or down-regulation? It is the pulsatile nature of secretion of hormone as most hormones are not always in the same level of secretion; it goes up and down in a normal way but in the example of epinephrine and norepinethrine it is abnormal condition so we need the up and down regulation. A good example for pulsatile secretion is cortisol [is secreted from adrenal cortex under the effect of ACTH(secreted from pituitary)] it is secreted more in the morning it makes you happy and alert and conscious, that is why when you travel to a far place for example the US(very big difference in time) you will suffer from changing the day with the night so your biological clock (Circadian rhythm) will secrete cortisol in the night which will make you alert and prevent you from sleeping.
3 Physiology 19 3 Half-life Time required for the blood [hormone] to be reduced to ½ reference level. So why is it important?? It is important because when you want to give a patient a drug you need to know the half-life of it, for example the half-life of insulin is 20 minutes so after 20 minutes it would be reduced to its half concentration so you know that you have to give it to the patient frequently (3 to 4 times a day according to the level of glucose in Note: insulin can be attached to some chemicals that prolongs its half-life the patient). The half-life of thyroxin is 7 days so we will give the patient once daily or twice every week or even once every week. Affinity and saturation of hormones Affinity (hormone binds to receptors with high bond strength): is the concentration at which this hormone is active if the affinity is very high then you need little amount of this hormone, if the affinity is too low then you need high concentration of this hormone. Km: it is the concentration of the substrate at which the activity is half maximum and it is a measure for affinity. Saturation (low capacity of receptors): if binding site are all occupied then no more hormone can bind (this is the same as carrier protein when it reaches its maximum velocity; no matter how much do you add the substance no increase in the velocity will take place). Hormones are best active when it is at its physiological limits, usually when we are talking about hormonal action we are talking about physiological action but sometimes we give hormones as drugs so here we will be talking about pharmacological action. For example if an old lady is suffering from arthritis then we will give her cortisol, so it is given to her as a pharmacological dose which sometimes causes side effects such as a moon-shaped face, obesity, osteoporosis and high glucose level. The mentioned effects won t be caused by a physiological dose but rather caused by a pharmacological dose. Receptors
4 Physiology 19 4 They are specific proteins, which are able to recognize and bind to corresponding ligand molecules (hormones for example), become activated, and transduce signals to next signaling molecule. What is the ligand? It is a small molecule that binds to a specific receptor; for example the hormone is a ligand that binds to a specific protein receptor. There are two types of receptors: "إذا كنا مدافعين فاشلين عن القضية فاألجدر بنا أن نغير المدافعين ال أن نغير القضية" غسان كنفاني 1) Receptors on the cell membrane; they are for water-soluble hormones (for peptides and proteins) and are either Glycoprotein or lipoprotein. There are three types of them: a) ion channel receptor b)g-protein system c) enzyme-linked system. 2) Receptors inside the cell, located in the cytosol or in the nucleus. And they are DNA binding proteins. They serve as receptors for lipophilic hormones(hormones soluble in lipids); the hormone diffuses through the membrane and binds to its receptor then they are translocated to the nucleus (if the receptor was in the cytosol) where they affect the DNA s transcription and translation Mechanisms of Hormone Action In order for a certain cell to respond to specific a hormone, then the target cell must have specific receptors for that hormone (this is called specificity). The response depends on two things; on the hormone, and on the target cell. And the receptors on the plasma membrane usually: - Activate a second messenger mechanics (lipophilic (lipid-soluble) hormones do not have 2 nd messengers). But what is the importance of the 2 nd messenger system? It is important in amplification of an original small signal, so if you have one hormone that produces 10 second messengers, then those 10 second messengers stimulate 10 protein carriers, and each one of them phosphorylates 10 proteins and so on. So we call this cascade or amplification. Now, the amplitude of the responses of the target cells depends on two things:
5 Physiology The concentration of the hormone. - And the abundance of target cell receptor. So, if we have a large quantity of the hormone but without receptors, then we ll get no action. And the same, if we have a large number of receptors but we don t have the hormone, then we ll also have no action. So we should have them both together. What are the types of membrane receptors? (1) Ligand-gate ion channels type. Here the receptor itself is an ion channel, so binding of the hormone to the receptor changes the permeability of this ion channel; either by increasing or decreasing the permeability of this ion channel. And these channels can be either cationic (like Na+ & K+) or anionic channels (like Cl-). This picture shows the binding of the neurotransmitter (which is a hormone by itself) to the ion channel. If this channel is a Na+ channel, then we ll have EPSP [excitatory post-synaptic potential]. While if this channel is a K+ or Cl- channel, then we ll have IPSP [inhibitory post-synaptic potential]. So it depends on the type of the channel, and depends on the permeability whether it increases or decreases. The receptor of actylcholine is a pentapeptide (composed of 5 peptides), if it switches in one way it closes, while if it switches in the other way it opens. And that depends on the presence of acetylcholine, if there is acetylcholine, then they ll open, if not, then they ll close. This is one type of ligand gated channels (2) G Protein-Coupled Receptors The second type of receptors is the G-protein [Guanylate binding protein] system.
6 Physiology 19 6 The G-protein is a membrane receptor, in fact it is an integral protein, and it has extracellular and intracellular binding sites. And this G protein is composed of α, β, and γ subunits intracellularly. So it has 7 helices and 3 subunits inside the cytosol (intracellular) - G protein refers to any protein which binds to GDP or GTP and acts as signal transducer. - G protein consists of three different subunits (α, β, γ - subunits) bound to GDP, and it is inactive in this form when they are all bound together. The α subunit has a GTPase activity that will break down GTP. And once it is bound to GTP, the α subunit dissociates. Liberty means responsibility. That is why most men dread it. George Bernard Shaw - Now the α subunit dissociates from the complex and is ready to do some action! It can go to a nearby channel and change its permeability which will have some effect on the cell, for example, opening or closing a channel may cause depolarization or hyperpolarization in the cells, and that may cause secretion or inhibition of secretion of a hormone. The α subunit can also go to a nearby enzyme like the adenylyl cyclase and activate it, and once adenylyl cyclase is activated, it converts ATP into cyclic AMP. Or the α subunit may activate guanylyl cyclase that converts GTP into cyclic GMP. Now cyclic AMP is a second messenger, it goes and activates protein kinase, and this protein kinase is called camp-dependent protein kinase, and it is also called protein kinase A.
7 Physiology 19 7 Once the protein kinase is activated, it has an intracellular role; it phosphorylates other proteins. Phosphorylation of other proteins may either activate on inactivate them. Or the α subunit might go directly to an enzyme intracellularly and directly activate it or inactivate it. Or the α subunit may go to the DNA and stimulates transcription of genes, that results in the formation of proteins. Now how can this system be broken down? how can we stop it? We should decrease the level camp, but how? By the activation of another system that is called camp-dependent phosphodiesterase system. The phosphodiesterase will convert camp into AMP, so the cascade will stop. The properties of binding of hormones to receptors: High specificity, that s why they have a high affinity High affinity Saturation Reversible binding, so the activity will depend on the concentration of the hormone and the concentration of the receptor. Special function model; increases metabolism or decreases it, and so on Receptor Types (AGAIN) Channel-linked receptors o Ionotropic Enzyme-linked receptors o Protein kinases >> phosphorylation o Neurotrophins G-protein-coupled receptors o Metabotropic Intracellular receptors (for lipid soluble ligands) o Activation by cell-permeant signals Special thanks to my sister and brother, you are always a great help to me Done by: Yomna Abu-Farsakh
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