C2006/F2402 '10 Outline for Lecture 23 --  (c) 2010 D. Mowshowitz  -- Lecture updated 04/22/10

Handouts:    23A -- Lactation
                    23B -- Thyroid Structure and function; hormone synthesis & regulation
                    23C -- Stress Response & TK receptors
                    23D -- Heart & Circulation

See end of Last Lecture (Section V) for 'How to Keep Track of Hormones'

I. Overview of Major Glands & Hormones, Cont.  Handout 22B, cont.

    A. Hypothalmus. For A-C, see notes of previous lecture, section III, starting with III-C-4.

    B. Posterior Pituitary

    C. Anterior Pituitary

    D. Structure of HT/Pituitary. See notes of previous lecture, section IV.

    E. Brief Aside on Heart & Circulation -- For set up of general circulation, see Handout 23D, bottom. Pictures at top and middle are for reference (FYI) only.

1. Structure of heart (FYI)   See handout 23D, top & middle, or Sadava Fig. 49.2 (49.3).

a. Orientation: Note all pictures of heart show person facing you, so "right" 1/2 of heart is on left of picture.

b. Structure: "Subway diagram" on top of handout shows what is connected to what, but no real anatomy.

c. Anatomy: Pictures in middle of handout show approximations of actual structures.

2. Overall view of circulation  -- 23D, bottom and Sadava p. 1045 (945).

a. There are 2 loops of circulation -- to lungs (pulmonary) and to body (systemic) -- see picture on bottom of handout. Different blood vessels go in parallel to various parts of body.

b. Arteries go away from the heart; don't necessarily carry oxygenated blood

c. Structure: Arteries and veins, arterioles and venules are surrounded by smooth muscle; capillaries are not. (This allows extensive exchange of gas and small molecules between capillary and surround.)

3. Portal Vessels

        a. Normal Set Up -- No direction connection between two organs. Blood goes through one organ, back to heart, through lungs, back to heart, and to second organ.  

b. Portal Vessels -- provide short cut from one organ to another; connect two capillary beds as in HT and AP. See handout 22B.

Note:  Gas exchange was discussed briefly in lecture 3 (see the section on the anion exchanger.) A more detailed discussion of Gas Exchange is in Lecture 23 of '05.  The details of this topic will not be covered in lecture and you are not responsible for them. A link is included if you are curious or studying for MCATs.

II. Details of HT/AP Axis

    A. Hormones of Hypothalamus

1. 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 (see above) that goes direct to anterior pituitary.

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)

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

2. Outputs (to PP):  Some cells in HT release hormones (ADH & oxytocin) from nerve endings in PP. Hormones are peptides; made in cell body, packaged in vesicles, vesicles travel down MT's to end of neurons, hormones released by exocytosis.

    B. Hormones of Anterior Pituitary

1. Table of Major Hormones of AP -- details below -- see handout 22B

Tropic (or Pseudo-Tropic) Hormone(s)
All are Peptides

Target Organ

Hormones/Secretions Made by Target Organ

ACTH (adrenal cortex tropic H.) or adrenocorticotropin

Adrenal Cortex

Glucocorticoids, Mineralocorticoids** & sex steroids*

Gonadotropins -- LH (Luteinizing H.) and FSH (follicle stimulating H.)#


Estrogens, androgens & progesterone*

TSH (thyroid stimulating H.) or Thyrotropin



GH (Growth H.) = somatotropin

Liver (& others)

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


Mammary Gland


* All lipid soluble hormones 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.

#FSH stimulates Sertoli & Granulosa cells; LH stimulates Leydig & Thecal cells.

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

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

(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 handout 22B & table above.

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

3. 'Other Hormones 'of ant. pit.

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

(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 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 (from AP)   Receptor & 1st Target   Secretion by 1st Target   Final Target
Tropic Hormone GPCR in endocrine gland endocrine (steroid or TH.) blood
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). 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 is relatively obscure. MSH may be involved in control of body weight as well as pigmentation.

(4). Protein Precursors: 'pro-hormones' & 'pre-pro-hormones':

(a). Many hormones are made as inactive precursors = pro-hormones. Example: pro-insulin. 

(b). 'pre-pro-hormone' = pro-hormone with its signal peptide still attached = sequence that gene codes for.

(c). 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,  typsin, fibrin, etc.).

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

    C. Regulation of HT/AP Axis      

1. General case:  See Sadava fig. 41.8 (42.8)

a. The cascade: 

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

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

2. Specific case: thyroxine production (See handout 23B)

a. The cascade:


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)

(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. See Sadava fig. 41.9  (8th ed)

(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). Note that levels of TH production (& levels of TSH & TRH) are regulated by TH, unlike case with insulin, which is regulated by [G] levels in blood, not the hormone itself.

    D. Production of Thyroid Hormone (aka Thyroxine or TH) -- see handout 23B or Sadava 41.9 (8th ed).

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 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. 

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.)

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

 III. Examples of how hormones and nerves co-operate to run a circuit. See handout 23A.

   A.  Lactation

1. Overall Loop: Suckling by baby milk ejection ("letdown) more suckling   more milk ejection etc. Loop continues until baby stops nursing.

2. Signaling Pathway: Suckling by baby stimulates nerve endings in nipple nerve signal to HT release of oxytocin and prolactin as follows:

a. 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.

b. 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.

3. Receptors. Oxytocin uses a GPCR; PL & GH (the pseudo tropic hormones) use tyrosine kinase receptors (TK receptors or RTKs). These are explained below.

Question to think about: what does the circuit look like here? What's the IC? The effector? Etc.

Try problems 7-15 & 7-19.

    B. Stress response   (Handout 23C.)

1. Phase one -- Nerve (Sympathetic) activity stimulates target organs (that are not glands) Direct response of heart, liver, lungs, etc.

2. Phase two -- Nerve (Sympathetic activity) activation of glands

a. Stimulate pancreas glucagon release stimulated; insulin release inhibited secretion of glucagon additional stimulation of some of same target organs

b. 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.

3. 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.

IV. Signaling with RTK's. How do RTK's Work? 

    A. Importance of Catalytic Receptors

1. What are they? Catalytic Receptors are surface receptors whose intracellular domain is an enzymatic domain (or binds to one)

2. How do they work? Ligand binding activates the enzymatic domain. The active enzyme modifies a cellular protein, which binds to or modifies other proteins, etc.

3. Types: The enzymatic domain is usually a kinase, often a tyrosine kinase. We will stick to receptor tyrosine kinases & TK linked receptors.

4. What signaling molecules use TK receptors?

5. Results: Activation of TK receptors often leads to changes in TF's and transcription. (Note this not the usual case with G-linked receptors -- their end target is usually not a TF.)

    B. Important Properties of Receptor TKs -- See handout 23C & chart below.

1. Receptor is usually a single pass protein 

2. Ligand binding usually leads to dimerization of receptors (Sadava fig. 15.6 or Becker 14-17)

3 Dimerization activates a TK in cytoplasmic domain of receptor or in separate TK (that binds to receptor).

4. Active kinase auto-phosphorylates itself. TK adds phosphates (from ATP) to its own tyrosines -- each subunit phosphorylates the others.

5. Other proteins are activated by binding to phosphorylated TK's. (Sadava fig. 15.10 (15.9), or Becker 14-18)

a. Direct Effect: Some proteins can be activated by binding directly to TK.

  • Example? PLC. Ligand binding to TK-linked receptor can activate a type of PLC IP3 & DAG etc.
  • This means that the IP3 pathway can be activated by both types of receptors -- GPCRs and TKs. 
  • The cAMP pathway (as far as we know) can only be activated by GPCRs.  

b. Indirect Effect: Some proteins are activated by binding indirectly -- these proteins bind to "adapter proteins" that are bound to the TK. How it happens: 

(1). Adapter proteins bind directly to the  phosphorylated TK (to the phosphorylated tyrosines)

(2). Additional proteins bind to the adapters 

(3). Binding to adapters activation of the additional "recruited" proteins.

(4). Most famous (infamous?) example is the small G protein ras. Why does anyone care about ras?

(a). Overactive form of ras (stuck in the activated 'on' form) can cause cancer. Implies normal ras involved in control of cell cycle. (More on ras in lect. 25.)

(b). Large % (about 30%) of tumors have overactive ras.

c. SH2 domains. Proteins that bind directly to TK have certain types of domains -- usually called SH2 binding domains. 

d. Recruitment. Note that the initial target protein(s) to be activated come to or are "recruited by" the TK; this is the opposite of the situation with most 2nd messengers where the messenger diffuses throughout the cytoplasm and "seeks out" the target protein to be activated. The recruitment method may be important in localizing the response to a particular part of the cell.

    C. A human example of TK receptor signaling:  FGF (Fibroblast growth factor) and FGF Receptor.  Significance of dimerization. See Becker figs.14-20 & 14-21 (14-19 & 14-20).

1. FGFR is a TK receptor  

2. FGF & FGFR needed for proper development as described in Becker chap.14. Failure of signal transmission (or premature transmission) causes developmental abnormalities. See Becker fig. 14-20 (10-20).

3. How can achondroplasia (a type of dwarfism), due to a defective FGF receptor, be dominant? See Becker fig. 14-20 (14-19), and box on handout 22B.

a. The general principle: TK receptor monomers must dimerize in order to act. If 1/2 the receptors (1/2 the monomers) are abnormal, most of the dimers that form are abnormal.

b. An important consequence: "lack of function" mutations in TK receptors are often dominant. (For an example see Becker figs. 14-20 & 14-21 (14-19 & 14-20). Dimers form, but they are inactive.

c. Definition: An abnormal allele like the one that produces the FGF receptor without a cytoplasmic domain is called a "dominant negative mutation." A dominant negative allele (or mutation) makes an inactive protein that disrupts function even in the presence of a normal allele (and normal protein).

d. Significance: What does the existence of a dominant negative mutation imply? It indicates that the gene involved probably codes for a protein that must polymerize in order to act.

e. This case: In a heterozygote for achondroplasia, 1/2 the FGF receptor (monomers) are defective, therefore dimers that form are defective.

(1). In the example shown in Becker & on handout,  the cytoplasmic domain of the defective receptors is missing. Dimers form, but most dimers are never activated -- the two monomers can not phosphorylate each other. (Fig. 14-19) Therefore the signaling is badly disrupted. (In the example shown in Fig. 14-20, the FGF is needed to turn on formation of certain embryonic tissues, so the mutant fails to form these tissues. This type of mutation is called a 'dominant negative' as explained below.)

(2). (FYI)  In most cases of human achondroplasia, the molecular explanation is different. In these cases, the mutation is in the transmembrane domain of FGF3 Receptor and dimers form, but act abnormally. (In these cases, the FGF signal is needed to turn on bone differentiation and turn off cell growth. Mutant dimers signal prematurely, so differentiation starts -- and cell growth stops -- before bones are long enough. This type of mutation is called a 'gain of function' mutation, because it works when it shouldn't.)

4. Dominant Negatives -- Some Additional Background

a. 'Dominant negatives' make a mixture of normal and abnormal protein.  They are 'negative' because the heterozygote is negative for function, not because it doesn't produce any protein. There is actually a mixture of normal and abnormal protein present. What's unusual is that the abnormal, inactive, protein 'gets in the way' and interferes with the working of the normal, active, protein. So overall, there is a lack of function in the heterozygote.

b. Negative mutations (those that produce inactive protein) are usually NOT dominant.  Most negative or "lack of function" alleles (or mutations) are recessive. If there is a mixture of normal and abnormal protein in the heterozygote, the normal, active, protein usually works (in spite of the presence of abnormal, inactive, protein). So usually, overall, there is NO lack of function in the heterozygote.

    D. How do GPLR's and RTK's Compare? -- See table below for reference for comparison of basic features of  TK or TK linked receptors and G protein linked receptors.  For TK's, see Sadava figs. 15.6 & 15. 10 (15.9) or Becker fig. 14-17 for structure and Becker 14-18 for signaling pathway.

Properties of Two main types of Cell Surface Receptors

                                          Type of Receptor 

Property of Receptor G protein Linked Receptor Tyrosine Kinase or TK Linked Receptor (RTK)
Structure Multipass (7X) transmembrane protein# Single pass  transmembrane protein##
What happens on ligand binding Change in conformation Usually aggregation (dimers)##
Receptor activates (binds to) G protein Self (other subunit) or separate TK
Nucleotide role in activation Replace GDP with GTP Add phosphate from ATP to tyr side chains
Activated TK or G protein subunit* binds to: adenyl cyclase or
phospholipase C or
ligand gated channels
Many dif. proteins, usually protein with SH2 domains**
Can bind a PLC IP3 etc.
Which 2nd messengers used? cAMP or IP3 etc. IP3, etc. (if any); not cAMP. Often does not use a 2nd messenger.
Receptors for Epinephrine,  ADH, glucagon (most endocrines) Insulin and most GF's such as EGF (many paracrines & autocrines)
Usually modify Enzymes, not TF's Transcription Factors
Affect Transcription? Not usually Often
How contact target? Broadcast Recruitment

# See Becker Fig. 14-4. 
## See Becker fig. 14-17 or Sadava 15.6 & 15.3.
*Either part, alpha or beta + gamma may be activator/inhibitor; G proteins can also be inhibitory
**SH2 = sarc homology 2 domain

Review problems 6-1 & 6-3

    E. Signaling Pathways all interrelate

1. Different 2nd messengers can influence the same enzyme/pathway. See problem 6-20.

2. Each signaling system can affect the others -- For example, Ca++ levels can affect kinases/phosphatases and phosphorylations can affect Ca++ transport proteins (& therefore Ca++ levels). See an advanced text if you are interested in the details.

3. The same signal (same activated TK receptor) may trigger more than one signaling pathway. For example, EGF can trigger both the IP3 pathway and the ras pathway. (Becker fig. 14-18).

Next Time
: We'll wrap up TK receptors, and then look at structure & function of the kidney.