Unit 1 Endocrinology

quiz 1

organocentric theory

neuro/endo evolved separately

neurocentric theory

endocrine evolved from CNS

APUD theory

both coevolved with amine precursors

supported by same embryonic tissue for certain glands and neural crest

but, not all glands come from that tissue

Paleocentric theory

endocrine came first

supported by the fact that E. coli has insulin

Berthold’s chicken experiments

showed that testes produced/secreted something that influenced secondary sex characteristics in males

negative feedback

eliminate stimulus

1. sense

2. control center signal effector

3. effector eliminates initial stimulus

4. control center stops effector

positive feedback

heighten effect of stimulus

ex: childrbirth - contractions cause more dilation cause more contractions

ovulation - developing oocyte releases hormones that stimulate signal further development of oocyte

nervous system

short-acting, discrete, NTs travel short distances

endocrine system

long-acting, diffuse, many target organs/tissues/cells, long distances

pheromones

use olfactory epithelium sensors

releasing pheromones cause immediate behavior changes in receiving organism

priming pheromones cause physiological changes in receiving organism

neuroendocine reflex

reflex neural stimulation followed by endocrine response

nipple stimulation - neuroendocrine reflex

1. causes PFR activation

2. prolactin released from ant. pituitary

3. milk production

4. stimulation causes oxytocin release, signal neurons in post. pituitary

5. release milk from ducts

redundancy

multiple hormones with same effect

ex: epinephrine and glucagon cause breakdown of glycogen

reinforcement

one hormone w/ multiple effects

ex: epinephrine causes increased heart rate, decrease digestion, break down glycogen

additive/synergistic effects

2+ hormones have same effect but more effective together

ex: growth hormone and insulin, type 1 diabetic children fail to grow normally even with normal GH levels

permissive/priming effects

need A for B to work

ex: norepinephrine cannot effect BP unless cortisol is present

negative/positive cooperativity

once one molecule is bound, binding receptor has increased/decreased affinity for that molecule

ex: in type 2 diabetics, once insulin is bound there is a lower affinity for more insulin to bind

neurohormone

neuron secretes hormone to bloodstream

4 types of hormone classes

steroid (from cholesterol, made in adrenal cortex/gonads)

peptide

amine (modified tryptophan or tyrosine)

modified fatty acid (derived from phospholipids)

steroid hormone structure

• 17C cholesterol derived backbone

• 4 rings A-D

21 C

pregnane

19 C

androstane

18 C

estrane

suffix for -OH

-ol

diol, triol

suffix for =O

-one dione, trione

regulation of cholesterol

1. diet

2. de novo synthesis from acetate

3. excretion in form of bile salts

cholesterol transport

packaged as LDL

bind to LDL - R

endocytosis by cell

esterified cholesterol

modified cholesterol, stored form

Steroid producing cells contain increased

mitochondria

smooth ER

cholesterol storage

necessary enzymes

steroid production - mitochondria

where cholesterol is converted to pregnenolone

steroid production - smooth ER

convert pregnenolone to androgens/estrogens

steroids cannot be stored in vesicles because they are

lipophilic, they will diffuse right through

steroidogenesis

cholesterol to pregnenolone

This is the rate limiting step

StAR transports inside mitochondria, then p450scc cleaves side chain and hydroxylases

steroidogenesis

pregnenolone to glucocorticoids

3 hydroxylation steps (11, 17, 21)

steroidogenesis

pregnenolone to progesterone

isomerase dehydrogenates the -OH

steroidogenesis

progesterone to mineralcorticoids

form aldosterone

3 hydroxy (11, 18, 21)

then dehydrogenate at C18

steroidogenesis

progesterone to androgen

C17,20 Lyase

steroidogenesis

androgen to estrogens

aromatase A ring, hydroxy at C17

steroidogenesis

androgen to testosterone

hydroxylation at C17

steroidogenesis

testosterone to DHT

reduction at C5

gonadal steroid regulation

stimulated by FSH/LH from ant/ pituitary

adrenal steroid regulation

aldosterone —> angiotensin II when BP drops

cortisol —> ACTH when stress increases

ACTH function

increases free cholesterol (hydrolyze esters)

increase StAR (transport to mitochondria)

increase p450scc binding (convert cholesterol to pregnenolone)

Release of steroids

diffuse into blood, there is a low storage capacity in the cell

Transport steroids

proteins from liver

1. plasma transport protein

2. sex hormone binding globulin

3. albumins (high capacity but low affinity)

binding proteins function

• delay inactivation of steroid

• decrease metabolic clearance rate (MCR)

• increase half life

Steroid degradation

occur in liver/kidneys

conjugation with sulfates/glucaronic acid to make the hormone water soluble and inactivate

Steroid signaling receptors

high affinity and high specificity

Hinge model for receptors

1. ligand binds —> receptor dissociate from HSP and change shape

2. Reveal DNA binding domain specific for DNA sequence

MOA for steroids

1. dissociate from binding protein

2. diffuse into cell —> cytoplasm —> nucleus

3. bind nuclear recepter

4. receptor changes shape/ loses HSP

5. translocation

6. bind HRE of DNA

7. inhibit/activate transcription

8. translation

peptide producing cell contains

more rough ER, golgi, storage vesicles

less smooth ER, mitochondria

protein synthesis steps

1. DNA

2. transcription

3. mRNA

4. RNA processing (5’ guanylate cap, poly A tail, splicing)

5. translation

6. post-translational modification

signal peptide

1. attaches to signal recognition particle of ER

2. Roug ER cleaves signal peptide once ther

secondary modification - peptide cleavage

make multiple proteins from precursor

ex: insulin require cleavage to fold correctly

ex: POMC gene - depending on the enzymes in the cell, can be cleaved into several peptide hormones

control of peptide secretion

stored in membrane bound vesicle

cannot diffuse across membrane

stimulus secretion coupling methods/steps

3 methods to stimulate - hormonal (GnRH —> FSH/LH), non hormonal (increase blood glucose) , nervous system (neuroendocrine reflex)

Steps

1. stimulus —> membrane depolarization

2. VG Ca2+ channels open, increase intracellular Ca2+

3. vesicles fuse w/ plasma membrane

4. Release of hormone via exocytosis

proteins move through blood suspended in plasma except for…

growth hormone

half life of peptide hormones

small : 2-30 minutes

large : 60 minutes

degradation of peptide hormones

nonspecific peptidases cleave at N/C terminus

specific peptidase cleaves specific amino acids

Protein hormone receptor structure (3 domains)

extracellular - N terminus, ligand binding

membrane spanning region - transduction to ICF

Intracellular domain - transduction to ICF, C terminus

MOA - peptides

1. bind extracellular domain

2. binding event transmitted to cell

3. generates signal transduction events within a cell

ion-channel linked receptor

ligand binds —> channel opens

ex: AchR —> Na+ channels open

Enzyme linked receptor

activates when hormone binds

ex: insulinR —> kinases —> phosphorylation cascade to inactivate/activate other proteins

JAK/STAT steps

1. hormone bind R, JAK binds

2. JAK phosphorylates tyrosine residues to make docking site

3. STAT proteins recruited to receptor/JAK docking site

4. STATS phosphorylated, form homodimers, then go activate transcription

GPCR pathway

1. ligan binding, R changes shape

2. transduction activates G-protein (GTP—>GDP)

3. GDP activates adenylate cyclase (ATP—>cAMP)

G-protein linked receptor structure

a subunit interact with adenylate cyclase

B + Y subunit bind hormone receptor

secondary messengers - cAMP

cAMP activates PKA —> PKA furthers amplification of signaling

secondary messengers - cGMP

analog to cAMP

no G protein

secondary messengers - Ca2+

binds calmodulin

activates kinase that phosphorylates other kinases

secondary messengers - phosphoionositide

activates G protein —> cleaves the molecule into DAG and IP3

DAG - activates kinase —> phosphorylation cascade

IP3 - stimulates Ca2+ release