Welcome back. Today we want to talk about the endocrine system. We only want to talk about it in general concepts or general terms. When we actually go through the endocrine system a little later in the course, we're going to look at very specific endocrine glands. But today we're going to look over the entire to give an overview of the entire system. The first thing is to contrast the endocrine reflex loop with local control. Secondly, we want to characterize hormone classes. Each hormone classified according to its chemical nature. Third, we want to explain the role of carrier proteins. In the circumstance where we have a hydrophobic molecule, it has to be delivered by the blood aqueous delivery system, to the tissues. Fourth, we want to explain the differences among the receptor types for the different classes of hormones. Fifth we wan to explain the differences in their stimuli. Then lastly, we'll explain differences in their regulation. Okay. There's quite a bit of things to go over, so let's start. The first thing is to recognize that this is one of the major homeostatic control systems of the body. The other system, of course, is the nervous system. But you also have local control systems. The local controls systems occur at the target cells themselves. Recall that the target cells are the cells that have receptors, that is, a protein that can recognize a specific chemical. We said in the homeostasis lectures that we have a situation where a chemical can be secreted from the first cell and it works on its neighboring cell, and that chemical is called a paracrine. But we can also have the cell secreting a chemical that works on itself. That chemical is called an autocrine. These chemicals are not considered to be hormones. They are secreted into the interstitial space where they work locally. The homeostatic control that we're talking about when we're talking about the endocrine system is that we have a cell that secretes it's chemical into the blood. The blood delivers the chemical, hormone, to the target cells. Those are the cells that have receptors for the hormone or for that chemical. All of the cells of the body will be bathed by these hormones. They are all going to see the hormone. but unless they have a receptor for the hormone, they can't recognize the hormone and will not respond to the hormone. The second thing that we have to remember about this system is that these chemicals are being secreted into the blood. The blood is effectively three and a half liters of plasma. You have three and half liters of fluid. This means the chemical will be diluted into this very large volume. Because of that, the chemicals (hormones) will be at very, very low concentrations. Because they're at low concentrations, picomolar or nanomolar range concentrations, they have to have very, very high affinity receptors sitting on their cell surfaces. The target cell has a high affinity receptor. The chemical, hormone, is in the blood. The concentration of the hormone is going to be very low or very dilute. So we have very low concentration or very dilute signals. This is in contrast to the nervous system, which is our other major communication system of the body. Here, the nerve secretes its chemical into a very tiny space, which is called the synapse. The nerve is almost butting up against its target cell. The synapse is a very, very small space. Consequently the amount of neurotransmitter released will be in very high concentration at the target cell's receptors. So the target cell receptors will have low affinity. Low affinity means that the binding of neurotransmitter to that receptor is very rapid. But it will come off very quickly from that receptor. So in the nervous system then, we have a high concentration of the neurotransmitter. The receptor on the target cell is going to have a low affinity receptor. One other thing we need to remember about the endocrine system is that these are ductless glands. The secretions from these glands, hormones, going straight into the capillary beds that profuse all of the endocrine cells. There are no ducts to take the hormone, away from the gland and deposit it at a distance. The second thing is that the endocrine glands regulate many of the homeostatic missions of the body. They regulate the sodium and water balance, calcium balance, energy balance, processes that cope with stress, growth and development, and processes that are associated with reproduction. And as we go through the course, we will talk about each of the endocrine systems that mediate each of these different homeostatic functions. That other thing about the endocrine system is that the concentration of the hormone is critical. If we have too high of a concentration, then we have too much of a stimulus. If there is too great of a stimulus, we can down-regulate the receptors so that the receptors then on the target cells are not available. On the other hand, if we have too low of a concentration, then there is not enough of the receptors are activated on the target cells. In this case, we don't get a big enough biological response. So the concentration of the hormone in the blood should be what's called eu- concentration. This is where it is at the normal concentration to get an adequate response from the receptor. The rate of the production of the hormone is the most regulated aspect. It can be regulated by both positive and negative feedback loops. The other thing about the hormone system is that the hormones are delivered by the blood. And because they're delivered by the blood, it is a very, very slow delivery. In the nervous system, the nerve is butting right up against its target cell, so the response is immediate. It's within seconds. But with the hormonal system, the response can be minutes to hours. So it's a much, much slower type of a response. The other thing about it is that the delivery of these hormones can be dependent on mass action because some of these hormones are bound to carriers. If the hormone is bound to its carrier, as shown here, then that hormone can come off from the carrier and become a free agent. Once it is free within the bloodstream, then it's able to bind to its receptor. The receptor may be located on the cell surface or within the cell. In the case of the hormones that are bound to carriers, these are usually steroid hormones. These are usually lipid soluble hormones. They have are bound to a carrier in order to be able to move through the blood stream. They're bound to a protein carrier which has low affinity so that the hormone can be readily pulled off the carrier to bind to the target cell receptor. The hormone is released from the carrier to bind to its receptor, which has high affinity. So the mass action equation then is pulled towards the receptor. This is what's known as a mass action law. Lastly, the concentration of the hormone will be governed by its rate of degradation or removal from the body. It can be degraded either in the liver or by the kidney, and excreted by the kidney. Okay. W have three different types of hormones which we classify by their chemical nature. The first are the peptide or protein hormones. These can be anywhere from three amino acids or bigger. These hormones are first synthesized on rough endoplasmic reticulum (RER) as what as known as the preprohormone. This is an inactive species. The preprohormone then, this protein, will be further cleaved, as it is packaged and moved to the Golgi. Once it is located in the Golgi, another organelle within the body, then it's cleaved to a prohormone. In some cases, the prohormone is active, but in most cases the prohormone is also inactive. In the Golgi, then, these prohormones are packaged into secretory vesicles. The secretory vesicles contain the stored hormone inside. The prohormone is now cleaved one more time to form the active species. So the prohormone then is cleaved to give us the active hormone. This occurs within the secretory vesicles. Endocrine cells that secrete the peptide or protein hormones, contain secretory vesicles packaged with the hormone. These secretory vesicles can sit in the cytoplasm for long periods of time. The'll sit there until there's a secretagogue, a signal, that comes to the cell and tells the cell to secrete the hormone. The cell then will have an increase in calcium, intracellular calcium, or an increase in intracellular cyclic AMP. Either of those signals, will cause, the secretion of these stored hormones from the cells. These peptide hormones are pre-packaged. Because they're pre-packaged, they can be released as needed. So they're synthesize, and they're waiting for the signal to be secreted. The other thing about these is that they are proteins, Once the peptide hormones are in the blood, they have a very short half life. So peptide hormones have short half lives. They do not require a carrier because they are soluble within the plasma. They are synthesized and stored. An example of one of these hormones is insulin. Insulin is made as a preprohormone. Insulin is packaged, and then it is cleaved as it moves from the rough endoplasmic reticulum to the Golgi. There it's packaged into vesicles. Once it moves into the vesicle, the proinsulin is cleaved. The cleavage section from the insulin molecule is called a C peptide. It turns out that the C peptide also has biological activity. The two are present in equal molar ratio within the vesicle. When insulin is secreted, the C peptide is also released into the blood. The second type of hormones are hormones which are derivatives of cholesterol. These hormones are called steroid hormones. They are made by the adrenal glands, by the gonads, and by the placenta of the pregnant female. These steroid hormones are not soluble in plasma. They are lipid soluble, so they have to be transported in the blood on carrier proteins. These hormones have to be synthesized on demand. They can not be stored within membrane bound vesicles within the cytoplasm. Because they're able to cross the membrane that surround vesicles. They're soluble in lipid. So when you need any of these hormones then, they have to be synthesized. Once they're synthesized then they have to be secreted. This means these hormones take a bit more time for them to increase in amount within the blood. The other thing is that they have to be transported on carrier proteins. They are bound to the carrier protein, which is made by the liver, Bound to the carrier protein, they are delivered to the tissues by the blood. They are pulled off of the carrier protein and then used within the tissues. Many times, these steroid hormones are converted to a more active species within the target tissues. We'll talk about conversion when we get to the specific instances. For example, testosterone, which is made in male testes is the male sex hormone. Testosterone can be converted to a much more higher active form, called dihydrotestosterone, or DHT. Testosterone can also be converted to estrogen, the female sex hormone. This occurs within tissue as well. So testosterone can be converted by an enzyme, either to DHT, or to estrogen, depending upon the target tissue. The last class of these hormones is the amino acid derivatives. What is shown here are derivatives of tyrosine. Epinephrine is one of these hormones. It's made in the adrenal gland. Epinephrine is soluble in plasma. It has a very short half-life of seconds to minutes. Epinephrine will bind to the same receptors, the adrenergic receptors, that the neuroepinephrine binds to. It acts as a backup system for the sympathetic nervous system. Tyrosine derivatives can also be made into thyroxine (T4) or into T3. Thyroxine which shown here, is the thyroid hormone. Thyroid hormones are insoluble in plasma. They are transported via carriers to their target tissues. They have a very long half life, because they are bound to the carrier. Their half lives are on the order of hours to days. And in fact, the half life of T4 is seven days. Interestingly enough, these hormones are converted in the target tissue. T4, shown here, has four iodine residues on it. It can be converted to T3, which is the other active species, by removing one of the iodines. Let's talk a little bit about the transport carriers. The transport carriers as I said, extend the life of the hormone in the blood and for the thyroid hormones is several days. The steroid hormones, testosterone and estrogen have half lifes on the order of 60 to 90 minutes. These carriers importantly sequester the hormone from its target cell. As long as the hormone is on the carrier and is bound to the carrier, it's not able to enter and to engage with its receptor. So, the only hormone that's actually active is going to be the free hormone. The free hormone is going to be in very, very small concentrations within the blood. Because the free hormone is not very soluble within the blood. It is released from the carrier locally at the tissue. Once free of the carrier, it can bind to its' receptor. The total concentration of the hormone reflects the free plus the bound. So as you look at the total concentration then by using an antibody you will see what's bound as well as what's free. But it's only the free that's going to be active. Why is this important? You could have an instance where you have an individual who is put on birth control pills. They are taking estrogen. Estrogen causes the liver to produce more carriers for thyroid hormones. IN this individual, the total amount of thyroid hormone circulating within blood can rise. The extra hormone is bound to this new carrier, to this extra carrier. But even though you have a large amount of hormone bound to the carrier it's the free hormone that's the important amount. So the person could have normal amount of free hormone, but very high amount of hormone bound to a carrier. They would be normal. We'll talk about this some more when we talk about the thyroid gland. Now these different classes of hormones also differ in their receptor types. The hormones which are soluble in plasma, are hydrophilic peptide derivatives. They bind to receptors which are present on the cell's surface. That's what is shown here. There are essentially three different types of receptors that they can bind to. These receptors are integral membrane proteins. They are inserted within the plasma membrane. The first is one where you have a tyrosine kinase linked situation. This is the receptor for growth hormone. What this means is that when the hormone binds to this receptor, an enzyme, tyrosine kinase is activated. Kinase puts a phosphate group on something. This kinase is recruited to the GH receptor. That actvates second messenger signaling. A cascade of events starts which changes the metabolism of the cell. In the second case is the receptor for insulin. The nsulin receptor itself is a tyrosine kinase. So binding insulin to its receptor activates the tyrosine kinase. A phosphorylation cascade starts which change again the metabolism of the cell. Again, it's a very rapid second messenger signaling within the cell. And the last receptor type is the G- coupled receptors. The G- coupled receptors are using, in some cases, adenosine cyclase to cause changes, metabolic changes within the cells. And again, we're activating second messenger cascades, which will then rapidly change the metabolism of the cell. this is the type of receptor that binds glucagon. We also have the steroid hormones and the thyroid hormones. They're both soluble in lipids. These two types of hormones can cross the plasma membrane and enter directly into the interior of the cell. Because they can enter into the interior of the cell, their receptors are inside the cells. These receptors bind to DNA, and activate gene transcription. That means they will change the type of messenger RNA, and proteins that are made by this particular target cell. They change the activity of the DNA. In every case, there are multiple types of receptors on a given target cell. For instance, the beta cell of the pancreas has receptors that regulate its secretion of insulin. Those receptors include receptors for epinephrine. There's also receptors for acetylcholine on that same beta cell. It's going to the net effect of these receptors and whether they're activated and how active they are, that determine what the outcome is from that given beta cell. The other thing to remember is that there are a large numbers of these receptors on the cell surface. There's not just one receptor on the cell surface, but many, many, many copies of receptors on the cell surface. And also many copies of the transcription factors, that is the nuclear receptors which are within these cells. Receptors for steroid hormones and for binding thyroid hormones. The target cell sensitivity depends on its receptor. First, the affinity of the receptors, as we said, has to be high affinity for these hormones because we have very low concentrations of the hormone. Secondly, the receptor number, the target cells that have very high numbers of receptors on its cell surface for a given hormone, and are very, very sensitive to that particular hormone. And then third, competition. Competition occurs when hormones that are very similar in structure, can bind to the same receptors. For instance, the mineral corticoid receptor. Cortisol can bind to it and aldosterone can bind to it. To prevent cortisol from binding to the mineral corticoid receptor, the target cell has a protective mechanism which inactivates cortisol. And lastly, saturation. This occurs when all the receptors that are present on the cell's surface are bound by the hormone. All the receptors are occupied. We have maximal activity at that time or maximal response from the target cell. It is sort of difficult to think about this today. This is all abstract. I'm giving you a "laundry list" of things to remember. These are the type of things where it's difficult to comprehend because we're not talking about a particular hormone or a particular activity. Let's go through and look at the different kinds of stimuli that can activate the hormones or the endocrine systems. The first of these is a neuron that's targeted by a stimulus. This neuron then secretes a hormone. It is it's called a neuroendocrine cell. What's an example? Consider the neuron that senses the concentration of sodium within the blood. As sodium rises within the blood, this particular neuron becomes activated. It secretes a hormone called anti-diuretic hormone. This hormone works on the kidney. It causes the kidney to move water from the presumptive urine back into the blood to dilute down the amount of sodium that's within the blood. This is called a neural control. The neuron is secreting from what's called a posterior pituitary, a part of the brain. In the second kind of a situation, we have a hormone, which is regulating a hormone, which is regulating a hormone, which is regulating another hormone. This cascade is seen when the stimulus is low plasma glucose. If we have low plasma glucose then the hypothalamus, again, the portion of your brain can sense that from the blood. It secretes the first hormone which is growth hormone releasing hormone. That works on the pituitary cell to secrete growth hormone. And the growth hormone then works on the liver, which is its target cell. The liver then, or the bone, are its target cells. So here we have one hormone, which is controlling another hormone, which is controlling a third. So we have a series of hormones. This is a complex negative feedback loop. In the last case, we have the stimulus directly activate the final gland. Consider the example, of low blood calcium level. Low blood calcium level activates the parathyroid gland. The parathyroid gland secretes parathyroid hormone. Parathyroid hormone works on bone. Bone then will release calcium. The rise in calcium is the negative feedback loop which removes our original initiating signal, low blood calcium. This can be very complicated. The other illustration I could have given for this last one is the pancreas which secretes insulin. Glucose rises in the blood causing insulin to be secreted from the pancreatic beta cell. Insulin works on the target cell which is muscle or fat to take the glucose up into the tissue. We are goindg to consider very complicated systems. Each will be discussed separately at a later time in this course. That's how we turn on the endocrine system. So how do we turn off the endocrine system? We can turn off the system both locally and systemically. So we can turn off the system locally at the gland itself. This would be through receptor desensitization. If we simply remove the receptor for the hormone in the target cell, from the cell surface for instance. If it's an insulin receptor, and we remove it from the cell's surface, then the target cell which is a skeletal muscle, cannot see the insulin, does not bind the insulin, and won't respond. The alternative is that you can degrade the actual receptor. So you can remove it from the target cell surface and degrade it. The type two diabetic is a situation where we had receptor desensitization. The type two diabetics is where that individual does not respond correctly to insulin. Insulin is present in the system, but the receptor is desensitized. Consequently the movement of glucose from the blood into the skeleton muscle cells is altered. The insulin response to remove a rise in blood glucose due to feeding is faulty. The other way of controlling this is through the negative feedbacks and that's obviously what we were just talking about, where if you have the stimulus, and that was if you had a high sodium within the blood and then we move water back by this hormone, anti diuretic hormone, then move water back to the kidney to dilute that sodium. We remove that initiating signal. That's simply a regular negative feedback system. Okay. So what are our general concepts? First is that we have peptide hormones. They are soluble in plasma. They bind to cell surface receptors. They're fast-acting and they're gonna have short half lives. Secondly, we have thyroid hormones and steroid hormones. These are insoluble in plasma, they act by intercellular receptors to change transcription, that is, to change the DNA expression, or the gene expression. They're slow acting, and they're gonna have long half lives. Third, we have binding proteins, that are called carriers, that regulate the hormone availability to the target cell. They'd regulate the physiologic function and the half lives. The carriers extend the half lives of these hormones. Fourth, the hormone releases under neural control, hormonal control, nutrient control, or ion control. So, we can have different types of signals which are going to regulate whether or not the hormone is going to be secreted, or be synthesized and secreted. Five, signaling is regulated by changing the plasma hormone concentration This is, by far, the most common site for regulation. But you can also change the target cell sensitivity. You can do so by removing the receptors from the cell surface, or, you can simply uncouple the receptors so that you combine the hormone to the receptor. But, it doesn't activate the second messenger signalling within the cell. So, it's effectively turned off; it's desensitized by its receptor. Okay, so we will come back and look at all of these different points, when we are dealing with the endocrine systems themselves, with all the different individual endocrine glands, much later in the course, okay. So see you then.