DSA Intro to Endocrinology

Question 1

Hs secreted by the hypothalamus

Answer 1

• thyrotropin releasing H
• corticotropin releasing H
• gonadotropin releasing H
• growth H releasing H
• somatostatin
• dopamine

Question 2

Hs secreted by the anterior pituitary

Answer 2

• thyroid stimulating H
• follicle stimulating H
• luteinizing H
• adrenocorticotropic H
• melanocyte stimulating H
• growth hormone
• prolactin

Question 3

Hs secreted by the posterior pituitary

Answer 3

• oxytocin

- ADH

Question 4

Hs released by the thyroid

Answer 4

T3
T4
calcitonin

Question 5

Hs secreted by the parathyroid

Answer 5

PTH

Question 6

steps involved in the synthesis of peptide Hs

Answer 6

1. primary AA sequence of the peptide is dictated by mRNA which is transcribed from the gene for that hormone:
   a. In the nucleus, the gene for the hormone is transcribed into an mRNA
   b. mRNA is transferred to the cytoplasm and translated on the ribosome to the first protein product, a preprohormone
   i. translation pf the mRNA begins with a signal peptide at the N terminus
   ii. translation ceases, and the signal peptide attaches to the receptors on the ER via docking proteins
   iii. translation then continues on the ER until the entire peptide sequence is produced
   c. signal peptide is removed in the ER, converting the preprohormone to prohormone
   i. prohormone contains the complete hormone sequence plus other peptide sequences which will be removed later
   d. prohormone is transferred to golgi apparatus and packaged into secretory vesicles
   i. in the vesicles, the proteolytic enzymes cleave peptide sequences from the prohormone to produce the final hormone
   ii. golgi also glycosylates and phosphorylates hormones
   e. final hormone is stored in secretory vesicles until the endocrine cell is stimulated

Question 7

from where are steroid Hs synthesized and secreted?

Answer 7

1. synthesized and secreted by the adrenal cortex, gonads, corpus luteum, and placenta

Question 8

what are the steroid Hs?

Answer 8

1. steroid hormones include: cortisol, aldosterone, estradiol and estriol, progesterone, testosterone, and 1, 25 dihydroxycholecalciferol

Question 9

where are steroid Hs derived?

Answer 9

1. all are derivatives of cholesterol which is modified by removal or addition of side chains, hydroxylation, or aromatization

Question 10

amino Hs–what are they? where are they derived from?

Answer 10

1. catecholamines—epinephrine, norepinephrine, dopamine; and thyroid hormones
2. all derivatives of tyrosine

Question 11

neural mechanisms

Answer 11

a. Secretion of catecholamines where preganglionic sympathetic Ns synapse on the adrenal medulla and, when stimulated, cause secretion of catecholamines

Question 12

negative feedback mechanisms

Answer 12

1. some feature of hormone action, directly or indirectly, inhibits further secretion of that hormone
2. example: hypothalamus secretes a releasing hormone which stimulates secretion of an anterior pituitary Hant. Pituitary H then acts on a peripheral endocrine gland to cause secretion of the H which acts on target tissues to produce physiologic action
   a. hormones feedback on the anterior pituitary and hypothalamus to inhibit secretion
3. long loop feedback—hormone feeds back all the way to the hypothalamic-pituitary axis
4. short loop feedback—anterior pituitary H feeds back on hypothalamus to inhibit release of hypothalamic releasing H
5. ultrashort loop feedback—hypothalamic H inhibits its own secretion
6. net result—H levels are judged to be adequate or high, further secretion of the H is inhibited
   a. when they are low, then secretion of H is stimulated

Question 13

positive feedback

Answer 13

1. some feature of the H action causes more secretion of the H
2. self-augmenting process

Question 14

estrogen and FSH–positive feedback

Answer 14

1. hormonal ex: estrogen on the follicle stimulating H and luteinizing hormone by anterior pituitary during menstrual cycle
   a. during follicular phase of menstrual cycle, the ovaries secrete estrogen which acts on anterior pituitary to produce a rapid burst of FSH and LH which both have effects on the ovaries: ovulation and stimulation of secretion of estrogen
   b. estrogen secreted from the ovaries acts on the anterior pituitary to cause secretion of FSH and LH and these cause more estrogen secretion

Question 15

oxytocin–positive feedback

Answer 15

a. dilation of cervix causes posterior pituitary to release oxytocin which stimulates uterine contraction which further dilates cervix and releases more oxytocin

Question 16

dose response relationship

Answer 16

a. the responsiveness of a target tissue to a H is expressed in the dose response relationship
i. in which the magnitude of the response is correlated with H concentration
ii. as H conc increases, the response usually increases and then levels off
iii. sensitivity—H concentration that produces 50% of the maximal response
1. if more H is required to produce 50% of the maximal response, then the target has had a decrease in sensitivity
iv. the responsiveness or sensitivity of a target can be changed in 2 ways:
1. by changing the number of receptors
a. greater number of receptors, the greater the maximal response
2. by changing the affinity of the receptors
a. the higher the affinity, the higher likelihood of a response

Question 17

down regulation of Rs

Answer 17

i. number of R or affinity has dec
1. may occur by dec the synthesis of new R, inc degradation of existing R, or by inactivating R
2. reduces sensitivity of the target tissue when H levels are high for an extended amt of time
3. as down reg occurs, the response to H declines, even though H levels are still high
4. can also refer to H’s effect on R for other related Hs

Question 18

up regulation of Rs

Answer 18

i. number of R or affinity has inc
1. may occur by inc synthesis of new R, dec degradation of existing R, activating receptors
a. ex: prolactin inc the number of its R on breast, GH inc the number of Rs in skeletal muscle and liver
2. H can also upregulate the Rs for other Hs

Question 19

G proteins

Answer 19

1. Alpha—can bind either GDP or GTP and contains GTPase activity
   a. When GDP is bound to the alpha subunit, the G protein is inactive
   b. When GTP is bound, the G protein is active and can perform coupling fcn
   c. Guanosine nucleotide releasing factors (GRFs) facilitate dissociation of GDP so that GTP binds more rapidly
   i. GTPase activating factors (GAPs) facilitate hydrolysis of GTP
   d. Can be stimulatory or inhibitory—Gs or Gi
   i. When GTP is bound to alpha(s), the Gs protein stimulates the effector enzyme
   ii. When GTP is bound to the alpha(i), the Gi protein inhibits effector enzyme

Question 20

adenylyl cyclase

Answer 20

i. Involves binding of H to a R coupling by Gs or Gi and then activation or inhibition of adenylyl cyclase
1. Leads to increases or decreases in intracellular cAMP
2. cAMP, second messenger, then amplifies the signal to produce the final physiologic actions
ii. H utilizes a Gs protein and the complex is embedded in the membrane so when no H is bound, the alpha(s) subunit binds GDP and is inactive; but when the H binds:
1. H binds to R on the cell membrane and produces a conformational change in the alpha(s) subunit (1) which produces 2 changes:
a. GDP is released from alpha(s) subunit and is replaced by GTP
b. Alpha(s) subunit detaches from the Gs protein (2)
2. Alpha(s)-GTP complex migrates within the cell membrane and binds to and activates adenylyl cyclase (3)
a. Activated adenylyl cyclase catalyzes the conversion of ATP to cAMP which serves as a second messenger (4)
b. Intrinsic GTPase activity in the G protein concerts GTP back to GDP and the alpha(s) subunit returns to inactive state
3. cAMP, via a series of steps involving activation of protein kinase A, phosphorylates intracellular proteins (5/6) and these then execute the final physiologic action (7)
4. intracellular cAMP is degraded to an inactive metabolite, 5’ AMP, by the enzyme phosphodiesterase, thereby turning off the action of the second messenger

Question 21

phospholipase C mechanism

Answer 21

i. Hs that utilize the phospholipase C (IP3,Ca) mechanism involves binding of a H to a R and coupling via a Gq protein to phospholipase C
ii. Intracellular levels of IP3 and Ca are inc and produces results
iii. The R-Gq-phospholipase C complex is embedded in the cell membrane and with no H bound to the R, the alpha (q) subunit binds GDP and is inactive, but when the H binds, it is activated
1. H binds to its R in the membrane and produces a conformational change in the alpha (q) subunit (1)
a. GDP is released from the alpha (q) subunit and replaced by GTP
b. Alpha (q) subunit detaches from the Gq protein (2)
2. Alpha(q)-GTP complex migrates to and binds/activates phospholipase C (3)
a. Activated phospholipase C catalyzes the liberation of diacylglycerol and IP3 from PIP2 (4)
b. IP3 generated causes a release of Ca from intracellular stores in the ER or SR which results in inc in intracellular Ca conc (5)
3. Ca and DAG activate protein kinase C (6)
a. This phosphorylates proteins and produces the actions (7)

Question 22

guanylyl cyclase and ANP

Answer 22

a. Atrial natriuretic peptide (ANP) and other natriuretic peptides act thru a R guanylyl cyclase mechanism
i. Extracellular domain of the R has a binding site for ANP and the intracellular domain of the R has guanylyl cyclase activity
ii. Binding of ANP causes activation of guanylyl cyclase and conversion of GTP to cyclic GMP
iii. Cyclic GMP then activates cyclic GMP dependent kinase which phosphorylates the proteins responsible for ANP’s physiologic actions

Question 23

guanylyl cyclase and NO

Answer 23

a. Nitric oxide (NO) acts thru a cytosolic guanylyl cyclase
i. NO synthase in vascular endothelial cells cleaves Arg into citruline and NO
ii. this new NO diffuses out of endothelial cells into nearby vascular SM cells where it binds to and activates soluble or cytosolic guanylyl cyclase
iii. GTP is converted to cyclic GMP which relazes vascular SM

Question 24

serine/threonine kinase

Answer 24

a. Cascade of events activates protein kinase A or C when there are adenylyl cyclase and phospholipase C mechanisms
b. Activated kinases then phosphorylate serine and threonine moieties on proteins that execute physiologic actions
c. In addition, Ca calmodulin dependent protein kinase and mitogen activated protein kinases phosphorylate serine and threonine in the cascade of events leading to biologic actions

Question 25

R tyrosine kinases

Answer 25

i. Receptor tyrosine kinases—intrinsic tyrosine kinase activity within the R mc
1. Have an extracellular binding domain that binds the H or ligand and an intracellular domain that contains tyrosine kinase activity
a. When activated by H or ligand, the intrinsic tyrosine kinase phosphorylates itself
2. One type of R tyrosine kinase protein is a monomer—nerve growth factor and epidermal growth factor Rs
a. Binding of a ligand to the extracellular domain results in dimerization of the R, activation of intrinsic tyrosine kinase, and phosphorylation of tyrosine moieties on itself and other proteins
3. Also have dimers—insulin and insulin like growth factor receptors
a. Binding of the ligand (insulin) activates intrinsic tyrosine kinase and leads to phosphorylation of itself and other proteins and the H’s physiologic actions

Question 26

tyrosine kinase associated R

Answer 26

i. Tyrosine kinase associated R—do not have intrinsic kinase activity but associate noncovalently with protein that do
1. Also have an extracellular domain, hydrophobic transmembrane domain, and an intracellular domain
a. Intracellular domain DOES NOT have tyrosine kinase activity but it noncovalently assoc with tyrosine kinase such as the JAK system
b. H binds to the extracellular domain and leads to R dimerization and activation of tyrosine kinase in the assoc protein (JAK)
c. Assoc tyrosine kinase phosphorylates tyrosine moieties on itself, H R, and other proteins
d. Downstream targets of JAK include members of STAT family which cause transcription of mRNAs and new proteins involved in the H’s actions

Question 27

MOA of steroid and thyroid H

Answer 27

1. Steroid H diffuses across the cell membrane and enters target cell (1) where it binds to a specific R protein (2) that is located wither in the cytosol or nucleus
   a. Steroid H R are monomeric phosphoproteins that are a part of a gene superfamily of intracellular Rs
   i. Each R has 6 domains
   1. Steroid H binds to the E domain near the C terminus
   2. Central C domain is highly conserved among different steroid H Rs and is responsible for DNA binding
   b. With the H bound, the R undergoes a conformation change and the activated H-R complex enters the nucleus of the target cell
2. The H-R complex dimerizes and binds to specific DNA sequences called steroid responsive elements (SREs)–at the 5’ region of target genes (3)
3. H-R complex has now become a transcription factor that regulates the rate of transcription of that gene (4)
   a. New messenger RNA is transcribed (5)
   b. mRNA leaves the nucleus (6)
   c. new mRNA is translated to new proteins (7) that have specific physiologic actions (8)
   i. nature of the new proteins is specific to the H and accounts for specificity of the H’s actions