BISC 307L 2nd Edition Lecture 18 Current Lecture Stress activates 2 types of neurons in the hypothalamus the sympathetic neurons that send excitation to the sympathetic preganglionic neurons and neurons that release corticotropin releasing hormones This activation results in excitation of the peripheral sympathetic system which results in the release epi and the release of ACTH from the anterior pituitary and consequently the release of cortisol from 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 inhibits inflammation and immune responses On the left you can see that stress activates other areas of the brain that contain neurons that use norepinephrine and CRH as transmitters These are the amine and peptide transmitters commonly seen in areas of the brain that respond to stress Norepinephrine neurons tend to mediate behavioral changes like arousal wakefulness and appropriate aggressive responses 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 Figs Thyroid 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 talk about when we talk about Ca levels On the right we see a single thyroid epithelial cell On top is the extracellular space and blood in capillaries On the bottom the yellow stuff is the Colloid In our normal orientation the basolateral side is the side facing upwards toward the capillaries and the apical side is facing the colloid Step 1 The cells secrete two forms of protein that together make up the colloid material into the colloid the most abundant is thyroid globulin shown by purple stick figure and it is rich in tyrosine residues They also secrete 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 iodine exchanger 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 on another 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 And if 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 away readily 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 binding globulin which binds t4 at a higher affinity than T3 They also have albumin which can bind and transport thyroid hormones 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 reaction so mostly T4 gets produced But when T4 diffuses into target cells they have varying levels of