UN2006/UN2402 -- 2017 -- Outline UN2006/UN2402 -- 2017 -- Outline of Lecture #17 -- Hormones & Homeostasis cont. -- Thyroid & Kidney Function (c) 2017 Deborah Mowshowitz, Columbia University, New York, NY. Handouts for 17: 17A -- Basic Processes in Kidney Tubule -- posted in CW handouts (posted copy may say 23A) 17B -- Kidney Structure (posted copy may say 23B) You will also need Handout 16D (thyroid). Copies will be provided. I. Details of AP Function A. Role in Hypothalamic -- Pituitary Axis 1. HT/Ant. Pit Axis -- 3 stages, a to c a. HT → hormones (releasing factors) that signal the AP. Hormones go direct to AP through special portal blood vessel. b. AP (anterior pituitary) → tropic hormones (ACTH, LH, etc.) that signal to target glands (endocrine tissue). More on tropic hormones below. c. Glands → lipid soluble hormones (steroids & TH) that control their target organs/tissues. Overall: (a) (b) (c) HT → releasing hormone → AP → tropic hormone → TARGET GLAND → hormone → TARGET TISSUE → action. 2. Example: How HT controls adrenal cortex secretion of cortisol. (Another example, how HT controls thyroid, is on Handout 16D.) (a) (b) (c) HT → CRH → AP → ACTH → ADRENAL CORTEX → cortisol → TARGET TISSUES → action (1). HT secretes releasing hormone (CRH = corticotropin releasing hormone) -- step a. (2.) Ant. Pit responds by secreting tropic hormone (ACTH = adrenal cortex tropic hormone; also called adrenocorticotropin) into general circulation -- step b. (3). Target Gland (Adrenal cortex) responds by secreting a steroid hormone (cortisol) -- step c. (Will this require synthesis of cortisol? Or just its release?) (4). Steroid hormone (cortisol) acts on its target tissues. (Where would the cortisol receptors be? Would they be GPCRs? TFs?) (5). Steroid hormones of HT/AP axis (cortisol, thyroid hormone, etc.) regulate their own production through negative feedback loops. (6). Reminder: Adrenal cortex produces other steroids (mineralocorticoids & sex file:///C|/Users/dbm2/Documents/COURSES/C2006/current-lectures17/lect17.17.html[3/27/2017 6:31:32 PM] UN2006/UN2402 -- 2017 -- Outline steroids ), but ACTH does not regulate their production. 3. Regulation of hormone production -- how negative feedback works a. For cortisol. Cortisol (and other hormones of the HT/AP axis) regulate their own production through negative feedback loops. (Cortisol is not only secreted in response to stress.) b. Not all corticosteroids have a neg. f. b. effect on the AP. Note that aldosterone (mineralocorticoid) does not exert neg. f. b. on production of ACTH. (Why does this make sense?) c. For Thyroid -- see handout 16D. Details below. d. General case -- see Sadava 40.7B (41.11). B. Hormones of Anterior Pituitary -- details 1. Tropic Hormones a. Made by ant. pit and influence other endocrine glands. All peptides b. Release: controlled by hormones from HT c. Effect on target tissue (1). Effect: Usually cause release of another hormone (2). Mechanism: All tropic hormones work through G protein linked receptors and cAMP. (3). What is released from target gland? Hormones released by targets are steroids or act like them (thyroxine). (4). Question: Where are the receptors (for the appropriate hormone) on the AP? Endocrine glands? Target cells? d. Three major tropic hormone types -- each type named after its target -- see table below. Tropic Full name Alternative Name Target Gland Hormone adrenocorticotropin or adrenal ACTH adrenal cortex tropic H corticotropin cortex follicle stimulating H, lutenizing FSH, LH gonadotropins gonads H TSH thyroid stimulating H thyrotropin thyroid gland See problem 7-4. (Skip choice 5 for now.) 2. 'Other Hormones 'of ant. pit. a. GH and prolactin -- "pseudo tropic" hormones -- both peptides. file:///C|/Users/dbm2/Documents/COURSES/C2006/current-lectures17/lect17.17.html[3/27/2017 6:31:32 PM] UN2006/UN2402 -- 2017 -- Outline (1). Structure & mechanism: Similar in structure to each other (homologous) and use a special type of TK receptor (2). Release: Release regulated by release/inhibitory factors from HT. (3). What is released from target cells? Stimulate production of secretions, but not from endocrine glands. (a). GH stimulates secretion of ILGFs GH stimulates liver (& possibly other tissues) to produce insulin-like growth factors (ILGF 1 & 2). ILGF's from liver are released into blood (act as endocrines). ILGF's from other tissues act as paracrines. GH has other effects as well. (b). Prolactin stimulates secretion of milk. PL stimulates mammary (exocrine) gland to produce milk. (Need oxytocin to eject the milk.) PL & oxytocin are part of a positive feedback loop -- the more suckling by baby, the more neuronal signal to HT, the more hormones secreted, and the more milk made and ejected. Final Hormone (from AP) Receptor & 1st Target Secretion by 1st Target Target GPCR in endocrine endocrine (steroid or Tropic Hormone → → → blood gland TH.) Pseudo Tropic Hormones GH (somatotropin) → TKR in Liver* → ILGFs → blood Prolactin → TKR in exocrine gland → milk → outside * GH also effects other tissues -- some respond directly and some make ILGFs that affect other tissues/cells. ILGFs make by tissues other than liver are paracrines. TKR = Tyrosine kinase receptor; GPCR = G protein coupled receptor Try problems 7-1 & 7-13. b. MSH (melanocytye stimulating H), endorphins & enkephalins. (1). Function: Function of these hormones is relatively obscure. MSH may be involved in control of body weight as well as pigmentation. (2). Synthesis (a). Common source: More than one hormone can come from cleavage of single peptide precursor file:///C|/Users/dbm2/Documents/COURSES/C2006/current-lectures17/lect17.17.html[3/27/2017 6:31:32 PM] UN2006/UN2402 -- 2017 -- Outline (b). pro-opio-melanocortin or pomC is precursor that is cut up to give ACTH and MSH etc. (c). Alternative ways of cleavage: Same precursor can be cut up different ways in different tissues and/or species. Note: this is alternative processing of a protein, not an RNA. (d). Protein Precursors in general: 'pro-hormones' & 'pre-pro-hormones': (1). Many hormones are made as inactive precursors = pro- hormones. Example: pro-insulin. (2). 'pre-pro-hormone' = pro-hormone with its signal peptide still attached = sequence that gene codes for. Removal of signal peptide after insertion in ER generates inactive 'pro-hormone' (pro-insulin). (3). Removal of a short stretch of the peptide from the pro-hormone converts inactive pro-hormone to active hormone. (4). Some enzymes are also made in an inactive forms (called zymogens) -- for example, trypsinogen, fibrinogen. Zymogen (or pro- hormone) has amino acids that must be removed to give fully active product (insulin, trypsin, fibrin, etc.). C. Summary Table of Hormones of Anterior Pituitary Tropic (or Pseudo-Tropic) Hormones/Secretions Made by Target Hormone(s) Target Organ Organ All are Peptides Adrenal Glucocorticoids, Mineralocorticoids** adrenocorticotropin = ACTH Cortex Sex steroids* Gonadotropins# -- LH & FSH Gonads Estrogens, androgens & progesterone* Thyrotropin = TSH Thyroid Thyroxine* = TH = mixture of T3 & T4 Liver (& Insulin-Like Growth Factors GH (Growth H.) = somatotropin others) (ILGF 1 & 2) = somatomedins Mammary Prolactin Milk Gland * All lipid soluble hormones (steroids & TH) travel through the blood attached to plasma proteins. **Production of mineralocorticoids is largely controlled by factors other than ACTH. Most sex steroids are made by the gonads. Only small amounts are made by the ad. cortex. #For reference: FSH stimulates Sertoli & Granulosa cells; LH stimulates Leydig & Thecal cells. Try Problem 7-2 & 7-4 if not yet done, but skip choice 5 (of 7-4) for now. Be sure you have a firm grasp of most of handout 16B (or your own equivalent) in order to keep all the hormones and glands straight. You may find it worthwhile to memorize the set up, even if you put an outline on your card for the next exam. II. Thyroid and Regulation -- see Handout 16D. file:///C|/Users/dbm2/Documents/COURSES/C2006/current-lectures17/lect17.17.html[3/27/2017 6:31:32 PM] UN2006/UN2402 -- 2017 -- Outline A. Regulation of HT/AP Axis. For general case, See Sadava 40.7B (41.11). 1. Specific case: thyroxine production a. The cascade: HT → TRH → AP → TSH → TARGET GLAND → TH → TARGET TISSUE → increase in BMR, etc. b. Regulation (1). Negative Feedback: TH inhibits production of both TSH and TRH. (Where are the receptors? On cell surface or intracellular??) Primary effect is at AP -- reduces response to TRH. (2). Two different types of goiter (enlarged thyroid) -- to treat, need to know which one it is! For a picture of a goiter, see Sadava fig. 40.12 (41.13) (a). When TH is low (hypothyroidism) -- Lack of iodine or other factor → low level of TH Low level of TH → lack of negative feedback to HT &/or AP → overproduction of TSH → goiter. (See picture in Sadava.) (b). When TH is high (hyperthroidism): Have high level of TH but still have too much stimulation of thyroid. Problem can be i. Over production of TRH and/or TSH (due to tumors, failure of feedback, etc.), or ii. Over stimulation of TSH receptors by other factors. See Graves disease below. (3). Graves disease = antibodies to TSH receptors act as agonists of TSH. (Case of (b-ii) above). Reminder: agonist = acts like -- or has same effect as -- normal ligand antagonist = blocks action of -- or effect of -- normal ligand (4). What regulates or controls hormone levels? It's different for TH & insulin. (a). Levels of TH production (& levels of TSH & TRH) are regulated by the hormone itself (TH). Same for cortisol, FSH, LH. (See Sadava fig. 40.7B (41.11). (b). Levels of insulin production are regulated by [Glucose] levels in blood, not the hormone (insulin) itself. (Insulin secretion may also be affected by signals from brain, anticipating a rise in blood [Glucose], but is not regulated by hormone itself.) Question: Is either signal molecule (insulin or TH) a 'regulated variable'? 2. General case: See Sadava fig. 40.7B (41.11) file:///C|/Users/dbm2/Documents/COURSES/C2006/current-lectures17/lect17.17.html[3/27/2017 6:31:32 PM] UN2006/UN2402 -- 2017 -- Outline a.