C2006/F2402 '08 Outline for Lecture 23 -- (c) 2008 D. Mowshowitz -- Lecture updated 04/23/08
Handouts From last time: 22A -- Thyroid hormone
New this time: 23A -- Lactation ; 23B -- Stress Response; 23C = Overall Kidney structure;
23 D = Structure/Function of Kidney Tubule
I. Hormones, cont.
A. Production of Thyroid Hormone (aka Thyroxine or TH) -- see handout 22A or Sadava 41.9 (8th ed).
1. Biochemistry: Structure of TH -- How modification and rearrangement of tyrosines in thyroglobulin (TG) leads to TH.
2 Cell Biology: How is thyroxine made & stored? How (& where) TG is made & TH released from it.
TH made in follicle of thyroid gland
protein (TG) made on RER → Golgi → vesicles
exocytosis of vesicles releases TG into lumen
I- taken up into gland; I added to tyrosines of TG in lumen; one modified tyrosine added to OH of another.
Modified TG stored in lumen of gland = reservoir of TH
TG taken up by cell from gland by RME. Result is degradation of TG in lysosomes → releases T4 or T3 (= TH)
TH diffuses out of cell across membrane. Acts like a steroid. (For structures see handout or texts.)
TSH stimulates virtually all of these steps.
3. 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.)
4. Newspaper article on role of Iodine and TH in development: 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.
Try problem 7-5 & 7-9. (If you have time, there are additional problems on this topic -- most of problem set 7. )
B. Examples of how hormones and nerves co-operate to run a circuit. See handout 23A.
a. Overall Loop: Suckling by baby → milk ejection ("letdown) → more suckling → more milk ejection etc. Loop continues until baby stops nursing.
b. Signaling Pathway: Suckling by baby stimulates nerve endings in nipple → nerve signal to HT → release of oxytocin and prolactin as follows:
(1). Oxytocin: HT → release of oxytocin from neuron endings post. pit. → contraction of myoepithelial cells (similar to smooth muscle) surrounding alveolus (milk producing section of mammary gland) → milk ejection from lumen of alveolus → more suckling → etc.
(2). Prolactin: HT → PIH (= DA) down and PRH (?) up in portal vessel → AP releases prolactin (PL) → stimulates inner layer of cells surrounding lumen of alveolus → promotes milk production and secretion of milk into lumen of gland.
Question to think about: what does the circuit look like here? What's the IC? The effector? Etc.
Try problems 7-14 & 7-18.
2. Stress response (Handout 23B.)
a. Phase one -- Nerve (Sympathetic) activity stimulates target organs (that are not glands) → Direct response of heart, liver, lungs, etc.
b. Phase two -- Nerve (Sympathetic activity) → activation of glands
(1). Stimulate pancreas → glucagon released stimulated; insulin release inhibited → secretion of glucagon → additional stimulation of some target organs
(2). Stimulate adrenal medulla → release of epinephrine → stimulation of same targets as sympathetic nerve activity & some additional targets -- hormones can reach where nerves can't go.
c. Phase three -- stimulate HT/AP axis to produce cortisol
HT in brain → releases CRH → AP → releases ACTH → adrenal cortex → produces cortisol → target organs → stimulation of breakdown of fats & protein for energy (sparing glucose for brain); inhibition of immune system.
Note that each additional phase is slower but involves additional degrees of amplification due to second messengers, transcription, etc.
II. Kidney Structure & Function (Handouts 23C & B). See also Sadava Sect. 51.4. & 51.5
A. Overall Function -- what does the kidney do?
1. Function: Controls water loss and determines what other specific components (including protons & other ions) will be excreted (lost in urine) and what will be retained.
2. What processes occur in kidney?
tubular secretion (addition of substances to the filtrate)
tubular reabsorption (removal of substances from filtrate)
control of volume.
We will do structure first (23C or Sadava fig. 51.7) & then how these processes occur (23D).
B. Overall structure -- see handout 23C or Sadava fig. 51.9
1. Kidney has medulla (inner part) and cortex (outer)
2. Functional unit = nephron (Sadava 51.7 )
3. Visible unit (in medulla) = Renal Pyramid = bottoms of many nephrons
4. Tops of nephrons in cortex
C. Structure of Nephron -- see handouts or Sadava fig. 51.7 & 51.9 . For EM pictures see Sadava 51.8. (We'll do the parts as we need them, but all are summarized here.)
1. Nephron itself -- parts in cortex
a. Bowman's capsule
b. proximal (convoluted) tubule
c. distal (convoluted) tubule
2. In medulla
a. Loop of Henle
b. Collecting duct (shared by many nephrons)
a. 2 sets in series
(a). form glomerulus inside Bowman's capsule
(b). function = filtration
(a). surround tubules
(b). vasa recta = part in medulla (surrounds loop of Henle)
(c). function in secretion (release of substances from cells into filtrate) & reabsorption (transport of substances from filtrate to cells)
b. How capillaries connected. Circulation goes as follows:
Artery (from heart) → afferent arteriole → glomerular capillaries → efferent arteriole → peritubular capillaries → venule → vein (back to heart)
D. Basic Processes
1. The 4 Basic Processes
(1). Occurs in glomerulus
(2). About 20% of blood liquid (plasma) enters Bowman's capsule = filtrate
(3). Filtrate contains no large proteins or cells
b. Tubular (selective) secretion: Material is added to the filtrate. Therefore filtrate carries high concentrations of certain dissolved materials (secreted by cells lining the lumen) -- removes waste, toxins from circulation.
Note: 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.
c. Tubular (selective) reabsorption: Material is removed from the filtrate. Therefore filtrate does NOT carry certain materials (which are selectively reabsorbed) -- conserves valuable materials; returns them to circulation.
d. Volume: Water loss is adjusted later using ADH. Therefore urine can be more (or less) concentrated than the plasma -- can vary concentration and/or volume to suit need. Water loss/conservation controls volume of body fluids -- plasma, extra cellular fluid, etc. (& blood pressure)
2. How does tubular secretion/reabsorption occur? Structure of cells lining tubules -- see handout 23D or Sadava fig. 51.12 (for a different example).
a. Tubules 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 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 tubule have different transporters/channels on luminal surface.
f. Cells in different parts of tubule (except maybe descending loop) all have the Na+/K+ pump on their basolateral surface. Other transporters may vary.
g. Depending primarily on which transport proteins are on luminal surface, cells secrete materials into lumen or reabsorb material from lumen.
h. Cells lining tubule do actual secretion/reabsorption but capillaries remove reabsorbed material or provide material to be secreted. Therefore (as shown on 23D, top left):
(1). Result of tubular reabsorption = net transfer from filtrate to capillary.
(2). Result of tubular secretion = net transfer from capillary to filtrate.
i. For an example of reabsorption -- see 23D, upper right. (Fig. 14-18).
Try problem 12-3.
D. Function of Nephron -- Let's follow some liquid through.
1. Filtration in glomerulus
See problem 12-6.
2. Reabsorption (of most substances) in proximal tubule
a. Many substances removed from lumen by secondary act. transport
(1). examples: glucose and amino acids
(2). Cross apical/luminal surface of epithelial cell by Na+ cotransport
(3). Exit basolateral side of cells into intersit. fluid by facilitated diffusion
(4). Process is similar to absorption in cells lining intestine
b. Na+/K+ pump on basolateral side keeps internal Na+ low.
c. Water follows salt.
3. Events in Loop of Henley and rest of tubules -- overall picture of state of filtrate
a. Definition: Osmolarity (Osm) = total solute concentration = concentration of dissolved particles = osmol/liter. (One osmol = 1 mole of solute particles.)
Examples: 1M solution of glucose = 1 Osm; 1M solution of NaCl = 2 Osm.
b. Events in Loop
(1). Osmolarity increases as filtrate descends due to loss of water
(2). Osmolarity decreases as filtrate ascends due to loss of salt; reaches min. value less than that of blood. Therefore can excrete urine that is hypo-osmotic (less concentrated) than blood.
(3). Net effect of going through countercurrent loop -- less volume, less total salt to excrete (even if filtrate and blood are iso-osmotic when done).
c. Events in distal convoluted tubule (& first part of coll. ducts) depend on aldosterone -- ald. promotes reabsorption of Na+ and water follows. (See handout 23D, top right.)
d. Events in collecting duct depend on ADH -- Osmolarity will increase (and volume decrease) in collecting duct if ADH (vasopressin) present and water removed. (Details below.)
4. Details of Loop of Henley (See Sadava 51.10)
a. Luminal cell membranes in descending loop and lower part of ascending loop are permeable to water.
b. Luminal cell membranes in rest of ascending are impermeable to water and pump NaCl from lumen to interstitial fluid. (See 23D.)
c. NaCl pumped out from ascending loop accumulates in medulla, forming a gradient of increasing osmolarity (outside the tubule) as reach bottom of loop = core of medulla.
d. Filtrate from proximal tubule loses water as it descends into medulla → NaCl stays in tubule → high concentration NaCl in tubule→ to be removed in ascending.
e. If NaCl diffuses into descending loop, it is carried around and pumped out in ascending = escalator effect.
f. Why called countercurrent? Because flow in two sides of loop is in opposite directions physically and with respect to osmolarity. First leg (descending) of loop removes water → higher osmolarity in filtrate; second leg (ascending) removes salt → lower osmolarity in filtrate.
See problems 12-1 & 12-2.
5. Distal Tubule and Collecting Ducts
a. Filtrate entering here is at minimum osmolarity
b. More water and/or Na+ removed under influence of aldosterone and ADH
c. Role/Mech. of action of ADH
(1). ADH (using cAMP) stimulates insertion of water channels/pores into membranes of collecting duct (and maybe late distal tubule)
(2). Water flows out ADH-stimulated channels (if in membrane) because of salt gradient in medulla.
(3). Diabetes insipidus -- result of no ADH or no response to ADH
d. Role of aldosterone
(1). Promotes reabsorption of Na+; water follows.
(2). Amount of Na+ reabsorbed due to aldosterone is small % of total, but adds up.
e. Question to think about: Where are the receptors for ADH? Aldosterone?
See problems 12-9, 12- 11 & 12-15.
Next Time: Regulation of Kidney function & Blood Pressure; then Intro to the Immune System.