C2006/F2402 '06 OUTLINE OF LECTURE #15

(c) 2006 Dr. Deborah Mowshowitz, Columbia University, New York, NY. Last update 03/19/2006 02:23 PM .

Handouts: Need 14 (Hormones Overall), 15A (Thyroid, catecholamines),15B (glands, organs) & (Homeostasis).

This topic is not covered in Becker. It is covered in Purves. If you want a more detailed treatment, any physiology book will do. There are lots of good physiology books available; the one by Sherwood has been used here for the last few years. The texts by Vander or by Silverthorn are widely available and are also quite good. There is an endocrinology book on line through Pubmed. Go to books to see the list of books available or to search by topic. Also don't forget about Kimball's biology pages.

I. Details of HT/Ant. Pit. Axis

    A. Hypothalamic Hormones

1. Inputs: Neuroendocrine cells in HT produce hormones -- in response to 3 inputs -- neuronal, hormonal, & local conditions. (HT has sensors for some variables such as temperature, osmolarity.)

2. Outputs (to AP): Some cells in HT release hormones from HT itself. (As vs. cells that connect to post. pit.)

a. Release hormones into portal vessel (connects two capillary beds) that goes direct to anterior pituitary. See Purves 42.7 (41.7) and handout 14.

b. Hormones are release factors. Hormones released by HT affect production/release of other hormones by ant. pit.

c. Affect on release -- 'release factors' can be stimulatory (RH's such as ACTH-releasing hormone) or inhibitory (IH's such as prolactin release-inhibiting hormone = PIH) For a complete list see Purves Table 42.2 (41.2).

d. All HT hormones (except PIH = dopamine) are peptides/proteins

3. Additional info on dopamine (DA) & related compounds  = catecholamines

a. Structures: See handout 15A for structures of  catecholamines = epinephrine (aka adrenaline), norepinephrine (aka noradrenaline), and dopamine. These are all modified amino acids derived from tyrosine. All water soluble. (Note thyroxine is also derived from tyrosine but is not a catecholamine; it is lipid soluble -- see below.)

b. Receptors: There are multiple receptors for all of the catecholamines. Receptors are classified by their ligands and response to drugs.

    (1). Dopamine has its own receptors, separate from the adrenergic receptors.

    (2). FYI: All adrenergic receptors  bind to both epi and norepi. Some receptor types bind better to (have higher affinity for) one, some to the other, some equally well to both.  Epinephrine acts mostly through beta adrenergic receptors; norepinephrine mostly through alpha adrenergic receptors.

c. Mechanism of action: All receptors for all catecholamines are G protein linked; effects of hormones on any particular cell type depend on (i) what receptors are present,  (ii) what G protein each receptor activates. Each G protein does one (or more) of the following: activate adenyl cyclase; inhibit adenyl cyclase; activate phospholipase C.  See Previous lectures & RQ for exam #2 for examples of different responses to epi due to diff. receptors.

    B. Hormones of Anterior Pituitary

1. Table of Major Hormones of AP -- details below -- see handout 14

Tropic (or Pseudo-Tropic) Hormone(s)

Target Organ

Hormones/Secretions Made by Target Organ

ACTH (adrenal cortex tropic hormone) or adrenocorticotropin

Adrenal Cortex

Glucocorticoids, Mineralocorticoids & sex steroids*

Gonadotropins -- LH and FSH

Gonads

Estrogens, androgens & progesterone*

TSH (thyroid stimulating hormone) or Thyrotropin

Thyroid

Thyroxine*

GH (Growth Hormone) = somatotropin

Liver (& others)

Insulin-Like Growth Factors
(ILGF 1 & 2) = somatomedins

Prolactin

Mammary Gland

Milk

* All lipid soluble hormones travel through the blood attached to plasma proteins.

2. Tropic Hormones

a. Made by ant. pit and influence other endocrine glands

b. Release:  controlled by hormones from HT

c. Effect on target tissue

(1). Effect: Usually cause release of another hormone

(2). What is released? Hormones released by targets are steroids or act like them (thyroxine)

(3). Mechanism: All tropic hormones work through G linked receptors and cAMP.

d. Three major tropic hormone types -- each type named after its target -- see handout 14A & table in last lecture.

See problem 7-4. (Skip 5 for now.)

2. Other Hormones of ant. pit.

a. GH and prolactin -- "pseudo tropic" hormones

(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? Stimulate production of secretions, but not from endocrine glands.

(a). GH stimulates liver (& possibly other tissues) to produce insulin-like growth factors (ILGF 1 & 2); ILGF's from liver released into blood (act as endocrines); ILGF's from other tissues act as paracrines. (GH has other effects as well.)

(b). Prolactin stimulates mammary (exocrine) gland to produce milk. (Need oxytocin to eject the milk.)

Hormone   Receptor & Target   Secretion by Target    
Tropic Hormone → GPCR in endocrine gland → endocrine (steroid or TH.) → blood
Pseudo Tropic Hormones            
    GH → 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

(3). What's the difference between endocrine & exocrine glands? See handout 15B.

(a). Exocrine Gland

  • When gland forms, epithelial layer leaves duct to outside.

  • Secretion from gland flows into duct → outside or lumen.

  • Examples:

(i) sweat, mammary & tear glands → secretion → outside

(ii) stomach glands → secretion → lumen.

(b). Endocrine Gland

  • When gland forms, epithelial layer pinches off leaving no duct

  • Secretion (hormone) from gland enters blood.

  • Example: gonads, pancreas, adrenal.

Try problems 7-1 & 7-13.

b. MSH etc.

(1). Common source: All come from cleavage of single peptide precursor (pro-opio-melanocortin or pomC) that is cut up to give ACTH and MSH etc.

(2). 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.

(3). Function: Function of these hormones relatively obscure. MSH may be involved in control of body weight as well as pigmentation.

Try Problem 7-2 & 7-4 if not yet done, but skip 5 (of 7-4) for now.

    C. HT/Anterior Pituitary Axis -- Set up & Regulation of overall circuit (HT → Ant. Pit. → target)

1. General case:  See Purves 42.8 (41.8)

a. The cascade: 

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

b. Regulation: Hormone (thyroxine, sex steroids, etc.) has negative feedback effect on  HT and AP. Why inhibit both?

(1). Feedback inhibits HT -- alters production of releasing/inhibiting hormones (changing signal to AP)

(2). Feedback inhibits AP response to signal from HT (by down regulating receptors); may also directly inhibit synthesis of tropic hormone.

(3). Both neg. feedback effects lead to inhibition of release of tropic hormones from AP  

2. Specific case: thyroxine production (See handout 15A; Purves fig. 42.8 (41.9)

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.

(2). Two different types of goiter (enlarged thyroid)

(a). When TH is low (hypothyroidism):  Lack of iodine or other factor → low level of  TH → lack of negative feedback to HT &/or AP → overproduction of TSH → goiter

(b). When TH is high (hyperthroidism): Can sometimes still have too much stimulation of thyroid even in presence of TH.  Problem can be over production of TRH and/or TSH (due to tumors, failure of feedback, etc.), or to 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) above). Reminder:

  • agonist = acts like -- or has same effect as -- normal ligand

  • antagonist = blocks action of -- or effect of -- normal ligand

(4). What does thyroxine do? Raises BMR and is needed during childhood for brain development.

(5). How is thyroxine made & stored? By modification and rearrangement of tyrosines in thyroglobulin (TG) -- see handout 15A.

(6). How is TG made & TH released from it ?

  • 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.)

(6). 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.)

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

II. Introduction to Physiology & Multicellular organisms -- How do you use hormones to control homeostasis?

    A. Single cell Life Style vs. Multicellular

1. Single celled organisms

a. Surrounded by external environment -- Can't change or regulate it

b. Have one basic function -- grow and multiply

c. Respond to external conditions (since can't change them) to maintain optimal intracellular state

(1). Pick up and/or dump what is necessary for metabolism

(2). Keep intracellular conditions (pH, level of amino acids, oxygen, etc.) as constant as possible and expend minimal energy by adjusting rates of transcription, enzyme activity, etc.

d. Note no specialization: each cell does all possible functions

2. Multicellular organisms & Homeostasis

a. Each cell in organism surrounded by internal environment. Extracellular fluid that makes up internal environment is composed of:

  • plasma = liquid part of blood = fluid between blood cells

  • interstitial fluid =  fluid between all other cells

b. Organism as whole can regulate composition of internal environment (milieu); therefore can maintain relatively constant external environment for each cell. Process of maintaining a relatively constant internal environment (of whole organism) = homeostasis.

c. Each cell has two basic functions

(1). Grow or maintain itself as above

(2). Specialized role in maintaining homeostasis of whole organism

d. Cells are Specialized. Maintenance of homeostasis requires co-operation of many different cell types, not just circuits within a single cell.

Summary of Above:

  Unicellular Organisms Multicellular Organisms
What surrounds cell? External environment Internal environment of organism
Can organism regulate what surrounds each cell? No Yes
How many functions of each cell? 1 2
Is cell specialized? No Yes

    B. Organization -- How are cells set up to co-operate in a multicellular organism?

1. Cells, Tissues & the 4 major tissue types  (5, if you count the blood separately) -- see lecture #4, & Purves 41.2 & 40.3 (40.2, 40.3, & 40.4).

2. Organs

a. Made of (different kinds of) tissues.

b. Example: lining of GI tract. Has layers -- epithelial, connective, muscle, and nervous tissue; these serve primarily for absorption (of material from lumen), support, contraction, and regulation respectively. (See handout 15B or Purves fig. 41.2 (40.2)) The blood (a type of connective) doesn't really fit in this classification -- serves for transport of materials in and out.

3. Systems -- Group of Organs → body or organ system. Work together to maintain homeostasis for some component. See Purves 41.1 (40.1). Number of systems depends on who's counting. Usual # is 8-12; see Purves Table 41.1 (40.1) for a list.

III. How is a component of the internal milieu regulated? Will do this next time if we don't get to it.

    A. Let's look at a specific example, namely blood glucose. The see-saw view. See handout 15B or Purves 50.19 (50.20).

1.  Have a regulated variable -- glucose level in blood.

2. Need a sensor (or receptor) -- to measure levels of regulated variable (glucose).

3. Need effector(s) -- to control levels of regulated variable (glucose) -- usually have one or more effectors that respond in opposing ways. In this case, effectors are liver (can both take up or release glucose from/to blood),  & adipose tissue and skeletal muscle (which can take up glucose from blood).

Note: The term "effector" is used differently in molecular biology and in physiology. In physiology, it is usually used to mean "a tissue or organ (like muscle or liver) that carries out an action and thus produces an effect." In this example, the effectors = structures that act to raise or lower the blood glucose. In molecular biology, the term "effector" is usually used to mean "a modulator of protein function." A modulator = a small molecule (like an inducer, enzyme activator etc.) that binds to a protein, alters the shape and/or function of the protein, and thus triggers an effect.

4. Have a set point -- the level the regulated variable (blood glucose) should be. Set point is also sometimes used to mean the level at which corrections (to raise or lower the value) kick in. 

In most cases, there is no significant difference between these two definitions of set point. In some cases, the desired value (first definition) and the value at which corrections occur (second definition) may be different. For example, there may be two cut-off points-- upper and lower, that bracket the desired level of a regulated variable. At levels above or below the respective cut-off points, messages are sent to the appropriate effectors to take corrective action. The term "critical values" is sometimes used instead of "set points" to describe the cut-off point(s).

5. Signaling -- need some signal system to connect the sensor(s) and the effector(s). Can be nervous &/or hormonal. Primary hormones in this case are insulin & glucagon.

6. Negative Feedback -- the system responds to negate deviations from the set point. (In positive feedback,  the system responds to increase deviations from the set point -- a small deviation triggers a bigger one, which triggers a bigger one and so on. The deviations get bigger and bigger until → boom!)

a. If [G] gets too high, effectors take G up from blood. (top half of seesaw diagram)

b. If blood [G] gets too low, effectors release G to blood. (bottom half of seesaw diagram)

7. Value of regulated variable does not remain exactly constant, but stays within narrow limits.

See problem 5-1 & 5-2 a & b.

Next Time: Another example and a more detailed look at the glucose circuit.