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Lecture 2

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PHGY 210
John White

Sarah Margareta Ibrahim Wednesday, January 9th 2013▯ PHGY 210 - Mammalian Physiology II Lecture 2 - Endocrinology (Part 2 of 6) Feedback control of Hormone Secretion (Example of Calcium Regulation) • Hormone secretion is precisely regulated by feedback mechanisms. • An excess of hormone, or excess hormonal activity, leads to a diminution of hormone secretion. • Conversely, a deficiency of hormone leads to an increase in hormone secretion The example below is negative feedback of regulation of calcium in the circulation - weʼll see • this again this image is just to go over the concept rather than the details. • Calcium in the circulation has to be tightly controlled. We know from physiology that the bodyʼs use of calcium in all of itʼs cells is more important than keeping the calcium in the bones. So maintaining calcium in circulation and its accessibility to the cells in the body is extremely physiologically important - itʼs maintained at a very narrow range under normal physiological conditions. When itʼs low, parathyroid release from the parathyroid goes up and then parathyroid hormone does itʼs thing in bone, kidney and gut. • Bone is your calcium repository, your kidneyʼs are your filters so a physiological decision is made - how much do we let go in the urine? How much are we going to keep in the circulation? And of course, the gut is where dietary calcium (cheese, eggs, milk etc.) is absorbed. • Under the influence of parathyroid hormone and downstream events circulating levels of calcium rise. At that point they start to impinge increasingly on the calcium receptors in the parathyroid and that shuts down parathyroid production. Thereʼs this constant sort of argument back and forth - goes down a bit, PTH goes up and • then it goes up, shuts it down and the result is itʼs homeostatic. Most endocrine systems function this way. Hormonal Feedback Mechanisms (Example of Control of Glucocorticoid Production) • Showing this example because itʼs the HP-end organ axis. Will see this several times. • So you have corticotropin releasing hormone (CRH) (*Note: “trope” is an attraction for something) released by the hypothalamus impinges upon the pituitary - you get adrenocorticotropic hormone (ACTH) released and that goes to interact with itʼs receptors on the surface of the adrenal glands and that leads to the production of glucocorticoids. • Glucocorticoid levels rise and you get a double negative feedback where you get inhibition of release of CRH and ACTH at the level of the hypothalamus and the pituitary. ▯ 1 Sarah Margareta Ibrahim Wednesday, January 9th 2013▯ Endocrine Glands and their Secretions The following sections (on the different endocrine glands - today weʼll look at the pituitary gland and the thyroid gland) will be structured like this: 1. Anatomic Location 2. Hormones Secreted 3. Chemical Nature of Hormones 4. Effects 5. Mechanism of Action 6. Control of Release▯ 7. Problems ▯ 8. Treatment A. The Pituitary Gland 1. Anatomic Location • Looks like a tiny little punching bag hanging off of the bottom of your brain • Two distinctly different tissues (or cell types): (1) adenohypophysis (a.k.a. anterior pituitary, or pars distalis) and (2) neurohypophysis (a.k.a. posterior pituitary, or pars nervosa). • Histologically (aka under the microscope), the anterior pituitary is endocrine tissue. • The posterior pituitary is neural tissue. *Aside: Summary of what we will go through in the next few lectures. Know this for the exam: ▯ 2 Sarah Margareta Ibrahim Wednesday, January 9th 2013▯ 2. and 3. Hormones secreted/Chemical Nature of Hormones • The posterior pituitary is in this list because the posterior pituitary is effectively an extension of the hypothalamus (it looks like itʼs separate but itʼs continuous with the hypothalamus). As far as this course is concerned, the posterior pituitary produces two hormones: 1. Arginine vasopressin (antidiuretic hormone) 2. Oxytocin These two are short peptides and somewhere back in evolution there was a gene duplication event where the primordial oxytocin vasopressin gene somehow was duplicated and then there was some form of evolution and now we have two hormones in a large number of organisms that have related structures but largely distinct physiologies. These are short peptide sequences so you have an oxytocin gene and arginine vasopressin gene. • Then there are the other hormones that are produced by the hypothalamus that impinge upon the anterior pituitary. All of them except for one is different. Prolactin- inhibiting hormone = dopamine. Most people know dopamine as a neurotransmitter but it has a double life - it can act as a hormone as well. Dopamine is derived from a free amino acid called tyrosine. There is no dopamine gene! There are enzymes that produce dopamine from tyrosine but there is no dopamine gene. All of the other guys are peptidic - theyʼre peptides (even TRH) meaning theyʼre all coded by genes. ▯ 3 Sarah Margareta Ibrahim Wednesday, January 9th 2013▯ *Aside: Posterior Pituitary Gland [Neurohypophysis] • Outgrowth of hypothalamus connected by the pituitary stalk. • Secretes oxytocin and vasopressin (a.k.a. antidiuretic hormone ‐ ADH). • Oxytocin and vasopressin synthesized in two hypothalamic nuclei (supraoptic nucleus and paraventricular nucleus *** Nucleus in this case refers to a set of neurons (cells) not an actual cell nucleus), whose axons run down the pituitary stalk and terminate in the posterior pituitary close to capillary blood vessels. Posterior pituitary is a cellular extension of the hypothalamus. • Because they are both peptidic hormones, they are produced as larger pre- pro- hormones (these sort of signaling barcodes that direct them towards the secretory apparatus). This processing takes place during a transportation process down the pituitary stalk such that by the time they get to the blood system - the capillary network at the base of the pituitary, theyʼre in their mature form. At some point, to get the thing secreted you have to have close apposition of the neuronal cells with the circulation and this is where this takes place. • Prohormones processed in secretory granules during axonal transport. • Mature hormones liberated from the carrier molecules, neurophysins. • Circulating half lives: 1‐3 minutes (not uncommon because if itʼs turned over rapidly its easier to control its levels - you want the signal when you need the signal and not when youʼre done with it) 4. Effects Oxytocin: • Males: no known function, although secreted by posterior pituitary??? Probably affecting behavior. Love? • Females: two main functions, both motor. (i) Parturition (child birth); uterus extremely sensitive to oxytocin at end of pregnancy (aka, the uterus is producing high concentrations of oxytocin receptors at the end of pregnancy) ▯ ‐dilation of the uterine cervix by fetal head causes reflex release of ▯ oxytocin. ▯ ‐oxytocin then causes uterus to contract, which assists the expulsion of ▯ fetus and later of placenta. (ii) Milk ejection. In lactating mother: response to the stimulus of suckling. ▯ ‐Oxytocin causes milk filled ducts to contract and squeeze milk out. Why would we want to have oxytocin to have a short half life? You donʼt want uterine contractions after youʼve given birth. Ouch. ▯ 4 Sarah Margareta Ibrahim Wednesday, January 9th 2013▯ B. Thyroid Gland 1. Anatomic Location • Located at the back of the trachea (sort of wraps around the trachea) • It has this these follicle structures that are filled with whatʼs called “colloid” • 15 to 20g • Varies size with sex, age, diet, reproductive state, etc. • Larger in females than males. • Only 3g of healthy thyroid needed to maintain euthyroid state (normal thyroid physiology) • Colloid: major component is thyroglobulin, a large protein of 700,000 Dalton (so it has 6500 amino acids so the coding region of the mRna is almost 20,000 bp long - itʼs huge!) • Only produces a few tyrosine residues • All of this that takes place is under the control of TSH (thyroid stimulating hormone) • It is a source of thyroid hormones thyroxine (T4) and triiodothyronine (T3). • T4 and T3 are split off the thyroglobulin, and enter blood where they bind to special plasma proteins. • Synthesis of thyroglobulin under control of TSH of pituitary gland. Thyroglobulin provides a type of storage for T4 and T3 prior to release. • 2. and 3. Hormones secreted/ Chemical Nature of Hormones • Thyroid hormones contain iodine • This introduces a problem because it means that iodine now becomes an essential part of the diet (thatʼs why you have sodium iodide in salt) • Availability of iodine to terrestrial vertebrates limited. • Cellular mechanisms developed for concentration, utilization and conservation of iodine in thyroid gland. Iodide is I itʼs ionic so itʼs not going to get through • the cell membrane so itʼs not going to be absorbed non-specifically by every other cell type in the body it has to be specifically transported across a membrane - for that you need a transporter. • Thyroid follicular cells are able to trap iodide and transport it across the cell against a chemical gradient (active transport). • Youʼve got T4 and T3. The T4 is produced if youʼve got a diiodonated tyrosine ring which is transferred on to another diiodonated tyrosine ring (see image). The T3 is produced if a monoiodonated tyrosine ring is transferred onto to a diiodonated tyrosine ring. You can also get, under conditions of hyperthyroidism, a certain amount of reverse T3 (which is a marker of hyperthyroidism but is not a biologically active molecule because it doesnʼt bind to the thyroid hormone receptor at any physiological concentration). • Synthesis of Thyroid Hormones ▯ 5 Sarah Margareta Ibrahim Wednesday, January 9th 2013▯ Iodide as it crosses the membrane is converted • to iodine (I2). That is the substrate that is used to... • Iodine (I2) used for iodination of tyrosine residues of thyroglobulin (TGB) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). • Oxidative coupling of two DIT forms thyroxine (T4), while oxidative coupling of one MIT with one DIT forms triiodothyronine (T3). • These hormones are stored linked to thyroglobulin. • Tate of all steps of T4 and T3 formation is increased (and controlled) by TSH levels. • Control of thyroid activity • Another negative feedback loop • Without TSH (or when TSH is low), thyroid has very low turnover of thyroid hormones. So not much is going on. • Synthesis and release of TSH controlled upstream by hypothalamic thyrotropin releasing hormone (TRH) - obviously produced by the hypothalamus. So TRH turns on TSH production goes to the thyroid, • interacts with the TSH receptors on the thyroid. Stimulates all aspects of the thyroid hormone production. Thyroid levels in the circulation go up and thereʼs a negative feedback loop that is set up whereby production of TSH in the pituitary and TRH by the hypothalamus are attenuated by rising levels of thyroid hormone. • When T4 and T3 in blood increase they exert a negative feedback at both hypothalamic and pituitary levels to decrease release of TRH and TSH. • TSH interacts with specific receptors located on follicular cells, leading to increased production of T4 and T3. • Example. The TSH receptor is one of those so called G-protein coupled receptor and TSH binding to cells in the thyroid leads to cyclic AMP (cAMP) and a series of intercellular second messenger events downstream of it. • Iodine Deficiency (nutritional) • What happens when this goes wrong? If the tryosineʼs canʼt be iodonated, youʼre not going to produce thyroid hormone. If youʼre not producing thyroid hormone, thereʼs no negative feedback loop. If thereʼs no negative feedback loop, TRH goes up and TSH goes up. So TSH starts pounding on the thyroid - “wake up!” but no oneʼs home. So the way that they thyroid responds is by becoming hyperplastic (it gets bigger) as a way to try and make more of this stuff that it canʼt make. When the supply of iodide is deficient, synthesis of thyroid hormones decreases • and T4 and T3 in circulation decrease. • Release of TSH increases and the thyroid follicular cells are constantly stimulated. •
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