UN2006/UN2402 -- 2017 -- Outline

UN2006/UN2402 -- 2017 -- Outline of Lecture #17 -- & Homeostasis cont. -- & 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 () → 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 → AP → tropic hormone → TARGET GLAND → hormone → TARGET TISSUE → action.

2. Example: How HT controls secretion of . (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 (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

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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 (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 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 -- "pseudo tropic" hormones -- both peptides.

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(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 (& possibly other tissues) to produce -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 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), & 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

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(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 , Mineralocorticoids** adrenocorticotropin = ACTH Cortex Sex steroids* Gonadotropins# -- LH & FSH Gonads , androgens & * 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 of TSH. (Case of (b-ii) above). Reminder:

= 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)

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a. The cascade:

HT → RH → AP → tropic hormone → TARGET GLAND → hormone → TARGET TISSUE → action.

b. Negative FB:

(1). Long Loop: Hormone from target gland (thyroxine, cortisol, etc.) has negative feedback effect on AP (& also in some cases on HT).

(2). Short Loop: In some cases, tropic or pseudotropic hormone also exerts negative feedback on HT. (Not significant in case of TH.)

B. Production of Thyroid Hormone (aka Thyroxine or TH) -- see handout 16D or Sadava fig. 40.11 (41.12).

1. What does thyroxine do? Raises BMR and is needed for normal alertness and reflexes. Needed during childhood for brain development. See In Raising the World's I.Q., the Secret's in the Salt This article is part of a series from the NY Times (2006). Articles in this series examine diseases that hover on the brink of eradication, and the daunting obstacles that doctors and scientists face to finish the job.

Here are two more recent articles on Thyroid Function from the NY Times: Prenatal Testing of Thyroid Debated Raising the World's IQ (an op ed)

2. Biochemistry: Structure of TH -- How modification and rearrangement of tyrosines in thyroglobulin (TG) leads to TH. (See handout.)

3. Cell Biology: How is thyroxine made & stored? How (& where) TG is made & TH released from it. Steps:

1. TH made in follicle of thyroid gland

2. protein (TG) made on RER → Golgi → vesicles

3. exocytosis of vesicles releases TG into lumen

4. Iodine taken up into gland;

5. Iodine added to tyrosines of TG in lumen; one modified tyrosine added to OH of another.

6. Modified TG stored in lumen of gland = reservoir of TH

7. TG taken up by cell from gland by RME.

8. TG is degraded in lysosomes → releases T4 or T3 (= TH)

9. TH diffuses out of cell across membrane. Acts like a steroid. (For structures see handout or texts.)

4. TSH stimulates virtually all of the steps listed above.

5. How does thyroxine travel through the blood? All lipid soluble hormones are attached to plasma proteins, either to general proteins or specific binding proteins for that hormone. T4 and T3 are transported by thyroxine-binding globulin, which is specific for thyroxine. Note: thyroglobulin is not the same as thyroxine-binding globulin. (Globulin just means globular, soluble protein.)

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Try problem 7-5 & 7-9. (If you have time, there are additional problems on this topic -- most of problem set 7. )

Next time: Wrap up of anything we don't get to, and then how the kidney uses all the transport process previously discussed to achieve homeostasis of body fluids.

III. Intro to Kidney Function (Handouts 17A & B). See also Sadava Sect. 51.4 & 51.5 (52.4 & 52.5).

A. Overall Function -- what does the kidney do?

1. Function: Maintains homeostasis of ECF volume and composition. How is this achieved? Controls water loss and determines what other specific components (small molecules and ions, including protons) will be excreted (lost in urine) and what will be retained. (ECF = extracellular fluid = plasma + interstitial fluid = liquid outside cells.)

2. What (controlled) processes occur in kidney?

filtration

tubular secretion (addition of soluble substances to the filtrate) = secretion into the tubule

tubular reabsorption (removal of soluble substances from filtrate) = reabsorption from the tubule

control of volume of urine = control of water loss in urine

B. Overview of Kidney Structure (slides & details next time)

1. Functional unit = nephron

2. Nephron = tube surrounded by polarized epithelial cells. Basic parts are

a. Bowman's capsule b. proximal (convoluted) tubule c. Loop of Henle d. distal (convoluted) tubule e. Collecting duct (shared by many nephrons)

3. Cells in different parts of nephron have different transporters -- carry out different processes

4. Capillaries of nephron -- 2 sets -- glomerular & peritubular

a. Overall: Artery (from ) → afferent arteriole → glomerular capillaries → efferent arteriole → peritubular capillaries → venule → vein (back to heart)

b. Two types of capillaries

Glomerular Capillaries -- no exchange; traffic in one direction only (into tubule)

Peritubular Capillaries -- usual exchange of materials between blood and IF/body cells.

C. Details of Basic (controlled) Processes

1. Overview

a. Filtration: Material moves from glomerular capillaries into tubule.

b. Secretion & Reabsorption: Materials moves between inside of tubule and inside of

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peritubular capillaries (surrounding kidney tubule).

2. The 4 Basic Processes (First 3 -- GF, TS, and TR, are shown on handout 17A)

a. Filtration (GF) :

(1). Occurs in glomerulus

(2). About 20% of blood liquid (plasma) enters tubule = filtrate

(3). Filtrate contains no large proteins or cells

b. Tubular (selective) secretion (TS) : Material is added to the filtrate.

(1): Terminology: Secretion is NOT the same as excretion.

Secretion = extruded by the cells into extracellular space (into filtrate, lumen, etc.).

Excretion = carried out of body in urine or feces.

(2). Result of secretion: filtrate (pre-urine) carries high concentrations of certain dissolved materials (secreted by cells lining the lumen) -- removes waste, toxins from circulation.

c. Tubular (selective) reabsorption (TR) : Material is removed from the filtrate.

(1). Result of reabsorption: Filtrate does NOT carry certain materials (which are selectively reabsorbed) -- conserves valuable materials; returns them to circulation.

(2). Removal of materials (reabsorption) can be controlled or not

Reabsorption of AA, glucose is not controlled -- all reabsorbed.

Na+ reabsorption (& K+ secretion) are controlled -- rates adjusted (by aldosterone) to maintain homeostasic levels of the ions. See below.

d. Volume Control:

(1). Water loss is adjusted at the end of the tubule using ADH. (details next time.)

(2). Water loss or conservation in tubule controls volume of body fluids -- volume of extra cellular fluid (= volume of plasma & IF, & therefore blood pressure).

(3). Urine can be more -- or less -- concentrated than the plasma. Concentration and/or volume can be varied to suit need.

(4). Urine volume is adjusted as a consequence of (2).

Q: Which variables here are 'regulated variables' and which are not? Is urine volume a regulated variable?

3. How does tubular secretion/reabsorption occur? Structure of cells lining tubules -- see handout 17A bottom or Sadava fig. 51.11 (52.11) for a different example.

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a. Tubules are lined by layer of polarized epithelial cells (similar to those lining intestine)

b. Materials must cross epithelial cells to enter or exit lumen of tubules.

c. Interstitial fluid separates epithelial cells and peritubular capillaries.

d. Epithelial cells have different proteins/channels/transporters on their two surfaces -- the apical or luminal surface (facing lumen) and basolateral surface (facing interstitial fluid and capillaries).

e. Cells in different parts of the tubule have different transporters/channels on their luminal surface.

f. All cells in tubule have the Na+/K+ pump on their basolateral surface. Other transporters may vary.

g. What cells transport (& in which direction) depends primarily on which transport proteins are on the luminal surface. Depending on transporters, cells can secrete materials into lumen or reabsorb material from lumen.

h. Cells lining tubule do actual secretion/reabsorption but peritubular capillaries remove reabsorbed material or provide material to be secreted. Therefore (as shown on handout 17A, top left):

(1). Result of tubular reabsorption (TR) = net transfer from filtrate to capillary = movement out of tubule = reabsorption from tubule.

(2). Result of tubular secretion (TS) = net transfer from capillary to filtrate = movement into tubule = secretion into tubule.

Try problem 12-3.

4. Example of reabsorption -- see 17A upper right. (Fig. 14-18). How Na+ is reabsorbed.

Q: How could K+ be secreted? What would you have to add/remove from the diagram?

5 Role of Hormones

a. Overall -- Hormones cause water and/or some remaining Na+ to be removed (reabsorbed from filtrate) at end of tubule (= in distal nephron)

aldosterone affects Na+ reabsorption (& K+ secretion) -- affects water reabsorption indirectly

ADH affects water reabsorption directly

b. Role of aldosterone in Na+ reabsorption

(1). Promotes reabsorption of Na+

(2). Stimulates virtually all steps of reabsorption -- all steps shown in 17A, upper right.

c. Role/Mech. of action of ADH -- next time.

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See problem 12-10. Next Time: Wrap up of kidney & hormones, and then intro. to immunology.

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