Lecture #17

C2006/F2402 '07 OUTLINE OF LECTURE #17

Handouts: Need 16B (Hormones Overall), 17A (Thyroid, catecholamines),17B (glands, organs)
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. Review of Major Glands & Hormones, cont.

A. HT and Pituitary

1. HT/Ant. Pit -- overview last time; more details below.

2. HT/Post. Pit. (Purves 42.5 (41.5).

a. Details of Structure/hormone release -- Cells of HT have bodies in HT and axons/terminals in posterior pituitary.

(1). Release hormones (neuroendocrines) from endings (terminals) in post. pit → blood supply.

(2). 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 = ADH (vasopressin) and oxytocin. Peptides are very similar in structure (homologous = share common evolutionary origin) but bind to different (G protein linked) receptors → dif. effects.

(1). ADH. Affects (primarily) water retention; has 2 names because discovered twice from different effects. Details of action to be described when we get to kidney. (Works through IP3 or cAMP.)

(2). Oxytocin. Affects milk ejection, uterine contractions -- works (at least in part) through IP3 to affect Ca⁺⁺ and therefore contraction

B. Other Major Glands & Hormones

1. Adrenal Medulla & Cortex See Purves 42.10 (41.11).

a. Cortex (epithelial)

(1). Stimulated by ACTH (tropic hormone from ant. pit.)

(2). Produces three major types of steroids = corticosteroids. For structures see Purves 42.11 (41.12) .

(a). Glucocorticoids. Ex: cortisol -- involved in long term stress response (after epinephrine wears off --more details later)

(b). Mineralocorticoids. Ex: aldosterone -- regulates salt balance (to be discussed when do kidney)

(c). Sex Steroids -- cortex produces low levels of sex hormones (both androgens and estrogens) in both sexes. That's how females get 'male' hormones and vice versa.

b. Medulla (nervous)

(1). Stimulated by nerves

(2). Is neural tissue

(3). Secretes compounds that can act as transmitters (when signal cell to cell) but act as hormones (neuroendocrines) here -- are released into the blood. Note same compound can act as a transmitter or a neuroendocrine. (Roles as transmitters to be discussed later.)

(4). Major hormone = epinephrine (adrenaline); also secretes some norepinephrine (noradrenaline).

(5). Receptors. Receptors for these hormones/transmitters are same adrenergic receptors (α & β) discussed previously.

2. Pancreas -- secretes glucagon and insulin -- Control blood sugar balance. Details next time.

3. There are other glands/hormones -- the list so far is not exhaustive but covers most of the major players. See texts for complete lists.

II. 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 16B

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 17A 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 (for epi and norepi).

(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 & problem 6-21 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 16B

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.)	Gonads	Estrogens, androgens & progesterone*
TSH (thyroid stimulating H.) or Thyrotropin	Thyroid	Thyroxine*
GH (Growth H.) = 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. 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 16B & table above.

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

2. 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	→	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

(4). What's the difference between endocrine & exocrine glands? See handout 17B.

(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.

(c) Both types get precursors for secretions from blood

Try problems 7-1 & 7-13.

b. MSH (melanocytye stimulating H) 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 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 form -- for example, trypsinogen, fibrinogen. Inactive form of inactive enzyme or 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. 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 17A; 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 for normal alertness and reflexes. Needed during childhood for brain development.

(5). How is thyroxine made & stored? By modification and rearrangement of tyrosines in thyroglobulin (TG) -- see handout 17A.

(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.)

TSH stimulates virtually all of these steps.

(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. )

III. 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 end of lecture #3 & start of 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 17B 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.

Next Time: How do Hormones control the internal milieu?