BISC 307L 2nd Edition Lecture 18 Current LectureStress activates 2 types of neurons inthe hypothalamus: the sympatheticneurons that send excitation to thesympathetic preganglionic neurons andneurons that release corticotropinreleasing hormones. This activationresults in excitation of the peripheralsympathetic system, which results inthe release epi and the release of ACTHfrom the anterior pituitary (andconsequently the release of cortisolfrom the adrenal cortex). These are both stress responses, and they do not overlap much in their time frames. Epinephrine is a rapidly-developing and short-acting stress hormone. Cortisol, on the other hand, is slower in developing its signal, which is more persistent. But they share a lot of their functions – for example, fuel mobilization from stores and how it is distributed in the body, and stimulation of the cardiovascular system.On top of that, epinephrine inhibits visceral function, and inhibits many of the functions that the PS system would enhance. And cortisol inhibitsinflammation and immune responses.On the left, you can see that stress activates other areas of thebrain that contain neurons that use norepinephrine and CRHas transmitters. These are the amine and peptide transmitterscommonly seen in areas of the brain that respond to stress.Norepinephrine neurons tend to mediate behavioral changeslike arousal, wakefulness, and appropriate aggressiveresponses like dilation of the pupils, defensive postures, etc.CRH neurons in these other brain areas tend to inhibit feeding,growth, and reproduction.There is interplay between right hand side (endocrine) and left hand (neural) side. You can see the negative feedback arrows that cross over between both sides. The idea is that taken as a whole, all these responses in the different areas of the brain and the peripheral endocrine system are adaptive and appropriate in stressful situations. They prepare the body an emergency response by shifting resources away from long-term investments, like feeding, growth, and reproduction, and shift it instead towards short-term survival behaviors and abilities. At the same time, they suppress responses of the immune system that might interfere with these life saving behaviors. Thyroid Hormone and Growth Hormone FigsThyroid Follicles:The thyroid is in neck, and it wraps around just in front of the larynx. Within the thyroid gland, the functional unit is the thyroid follicle. Thyroid follicles are spherical, there is a one cell thick layer surrounding a sphere filled with water. That is called a colloid cell. There are C cells that secrete calcitonin, which we will talkabout when we talk about Ca levels.On the right we see a single thyroidepithelial cell. On top is the extracellularspace and blood (in capillaries). On thebottom, the yellow stuff is the Colloid. Inour normal orientation, the basolateralside is the side facing upwards towardthe capillaries, and the apical side isfacing the colloid. Step 1: The cells secrete two forms ofprotein that together make up thecolloid material into the colloid –themost abundant is thyroid globulin,shown by purple stick figure, and it isrich in tyrosine residues. They alsosecrete synthetic enzymes that are necessary to make the thyroid hormone out of this stuff. So all this synthesis happens extracellularly in the colloid, not in the cell. Step 2(up top): These cells also secrete iodide ions, which are brought in from the blood across the basolateral membrane at the top by a sodium iodide symporter. This is the only place in the body where there is a known requirement for dietary iodine. We take up iodine against its conc gradient, and then transport it across the apical membrane by using Pendrin, a chloride iodineexchanger. This will allow the simultaneous movement of iodine in one direction, and chloride in the other. So it is selectively neutral and is served by diffusion, whichever way the conc ion goes for each ion. By means of these 2 transporters, iodine is brought in and concentrated in the colloid material. Now we have all the materials necessary to synthesize thyroid hormones. Step 2(below): Thyroid peroxidase takes the iodine ion and adds it to a tyrosine. That tyrosine is part of the amino acid sequence for the thyroglobulin protein. So the iodinated tyrosine is added to the thyroglobulin protein to form MIT. Thyroid peroxidase can do this twice – it can add another iodide to MIT to make DIT. So you end up with a mixture of MIT and DIT as part of the structure of the protein. Then, other enzymes take a DIT and either another DIT or a MIT(onanother place in the chain or in another thyroglobulin molecule) and covalently link them together. And when you have two DIT’s joined covalently, you get tetraiodothyronine, or T4. Andif one of the DIT’s gets coupled to an MIT, you get T3. You can see that this forms an insoluble gelatinous colloid material – everything is covalently linked and crosslinked within the structure of the protein and with other different protein molecules. It is all precipitated protein that are crosslinked by thyronine bridges. However, this allows it to be insoluble, which is important because T3 and T4 themselves are highly lipid soluble. If they were not openly bound to the backbone of this protein, they would diffuse awayreadily and easily. So this is an unusual way to store a lipophilic hormone. These two are the only lipophilic hormones made in advance and stored.Step 4: When the hormone is stimulated for release by an anterior pituitary hormone, it will phagocytose a small amount of the colloid material and internalize it into the cell, where it is processed. And when the peptide bonds that are holding the T3 and T4 are cleaved(step 5), T3 and T4 are liberated and they take off and diffuse out the cell(step 6). That is how the hormone is made, stored, and released. Do they have binding proteins in te plasma to transport them? Yes, they have specific and nonspecific ones. Specific= thyroid bindingglobulin, which binds t4at a higher affinity thanT3. They also havealbumin, which can bindand transport thyroidhormones. Thyroid Hormones:Don’t memorize the structure. They look like 2 tyrosines stuck together with iodine. If you take an iodine off the top of T4, it becomes T3. Why are there two thyroid hormones? Are they both released? In humans, most of the circulating thyroid hormone is in the form of T4. Back in the thyroid gland, joining a DIT and another DIT is a preferred