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Berthold
Endocrine
Experiment
Removereplacementinjection
Objectives
1. Chemical classes of hormones
2. Biosynthesis of a particular hormone
3.Transport of the hormones
4.Recognition & signaling of the hormone
5.Functions of the hormones.
6.Degradation of the hormone.
Endocrine Methods
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Remove-replacement-injection
Purification and cloning
Synthesis and production of hormone
Test biological activity with pure hormones
Development of antibodies
Localization by immunocytochemistry
Establish assays (RIA)
Microarray,deep sequencing, proteomics
Knock-out/Knock down/mutants
Hormone Types/Functions
Three structural divisions:
1) Amines--H2O sol. (small--AA)
catecholamines and thyroid hormones
2) Steroids--lipid sol. cyclic
hydrocarbon derivatives from cholesterol
3) Peptide/protein -- H2O sol. largest,
complex
Amines
• Hormones derived from tyrosine and
tryptophan.
• Include hormones secreted by adrenal
medulla, thyroid, and pineal glands.
Thyroid Hormones
• Tyrosine derivatives
bound together.
• Contain 4 iodine
atoms (T4).
• Contain 3 iodine
atoms (T3).
• Small, non-polar
molecules.
– Soluble in plasma
membranes.
Steroids
• Lipids derived from
cholesterol.
• Are lipophilic
hormones.
–
–
–
–
Testosterone
Estradiol
Cortisol
Progesterone
Peptides/Proteins
• Chains of amino acids (< 100 amino acids
in length).
– ADH
– Insulin
• Long polypeptides (>100) bound to one or
more carbohydrate groups.
– FSH
– LH
Biosynthesis of Peptides and Protein Hormones
DNA (The gene)
RNA (Primary transcript)
RNA processing
mRNA
translation
Pre-(Pro)-hormone
Proteolysis via signal peptide cleavage
Pro-hormone
Proteolysis via second modification
Glycosylation
Hormone
phosphorylation
Proopiomelanocortin (POMC) gene
5’
5’
N
1
Signal
peptide
3’
3’ mRNA
2
3
4
4
ACTH
5
6
7
6
C
7
Products in
corticotrophic cell of the
anterior pituitary
b-lipotropin
6
g-MSH a-MSH CLIP g-lipotropin
8
Products in the
intermdeiary gland
b-endorphin
b-MSH MET-enkephalin
Classification of chemical
communication systems
1) Autocrine--secretion that
affects the same cell which the
secretion originated
Ex: Adrenergic nerve endings
2) Paracrine--secretion that
affects neighboring cells
Ex: Inflammatory response
3) Endocrine--a secretion of a
chemical substance that is
released into the blood and
affects a distant target
4) Exocrine--secretion of a substance that is
released onto surface of animal--including
internal structures
Exocrine Glands/tissues:
--possess ducts
--salivary glands, intestinal
epithelium, secretory cells in
stomach, and secretory cells
of the liver and pancreas
Endocrine Glands/tissues:
--lack a definite duct
--Adrenal gland, GI tract,
heart, kidney, ovary,
pancreas, thyroid, pituitary,
placenta, testes, and thymus
Hypothalamus
Bone
Hypothalamus
Optic
chiasm
Anterior
lobe of
pituitary
Connecting stalk
(infundibulum)
(b)
Posterior
lobe of
pituitary
(a)
Anterior
pituitary
Posterior
pituitary
Fig. 7-8, p.265
Anterior and posterior pituitary glands.
Posterior Pituitary
• Also called the neurohypophysis.
• Formed by down growth of the brain during
fetal development.
• Is in contact with the infundibulum.
• Nerve fibers extend through the
infundibulum.
Anterior Pituitary
• Master gland (also called adenohypophysis).
• Derived from a pouch of epithelial tissue
that migrates upward from the mouth.
• Consists of 2 parts:
• Pars distalis: anterior pituitary.
• Pars tuberalis: thin extension in contact with
the infundibulum.
Hypothalamic Control of
Posterior Pituitary
• Hypothalamus produces:
– ADH: supraoptic nuclei.
– Oxytocin: paraventricular
nuclei.
• Hormones transported
along the hypothalamohypophyseal tract.
• Stored in posterior
pituitary.
• Release controlled by
neuroendocrine reflexes.
Posterior Pituitary
(neurohypophysis)
--releases
neurohormones
1) antidiuretic
hormone
(vasopressin)
2) oxcytocin
Larhammar et al, Ann. N.Y. Acad. Sci. 1163: 201–208 (2009)
Hypothalamic Control of the
Anterior Pituitary
• Hormonal control rather than neural.
• Hypothalamus synthesizes releasing
hormones and inhibiting hormones.
• Hormones are transported to axon endings of
median eminence.
– Delivers blood and hormones to anterior
pituitary via portal system.
Hypothalamic Control of the
Anterior Pituitary
• Hormones secreted
into the
hypothalamohypophyseal portal
system regulate the
secretions of the
anterior pituitary.
Feedback Control of the
Anterior Pituitary
• Anterior pituitary and hypothalamic
secretions are controlled by the target
organs they regulate.
• Negative feedback inhibition by target
gland hormones.
Feedback Control of the
Anterior Pituitary
• Negative feedback at 2 levels:
– The target gland hormone can act on the
hypothalamus and inhibit releasing hormones.
– The target gland hormone can act on the
anterior pituitary and inhibit response to the
releasing hormone.
Fig. 7-11, p.269
Fig. 7-12, p.270
Water vs. Lipid
Water soluble
hydrophilic
external (2nd mess.)
external receptors
short half-life
intermediary resp.
protein activation
Lipid soluble
hydrophobic
internal
cytoplasmic rec.
long half-life
Long-term resp.
gene activation
Mechanisms of Hormone
Action
• Hormones of same chemical class have
similar mechanisms of action.
– Location of cellular receptor proteins.
• Target cell must have specific receptors for
that hormone (specificity).
• Hormones bind to receptors with high bond
strength (affinity).
• Low capacity of receptors (saturation).
Hormones That Bind to
Nuclear Receptor Proteins
• Lipophilic steroid and thyroid hormones
bound to plasma carrier proteins.
• Hormones dissociate from carrier proteins to
pass through lipid component of the target
cell membrane.
• Receptors for the lipophilic hormones are
known as nuclear hormone receptors.
Nuclear Hormone Receptors
• Function within cell to activate genetic
transcription.
• mRNA directs synthesis of specific enzyme
proteins that change metabolism.
• Receptor must be activated by binding to hormone
before binding to specific region of DNA called
HRE (hormone responsive element).
– Located adjacent to gene that will be transcribed.
Mechanisms of Steroid
Hormone Action
• Steroid receptors located in
cytoplasm.
• Bind to steroid hormone.
• Translocates to nucleus.
• DNA-binding domain binds
to specific HRE of the
DNA.
• Dimerization occurs.
• Stimulates transcription.
Mechanism of Thyroid
Hormone Action
• Receptor proteins located
in nucleus.
• T3 binds to ligand-binding
domain.
• DNA-binding domain can
then bind to the half-site
of the HRE.
• Other half-site is vitamin
A derivative 9-cisretinoic acid.
• Two partners can bind to
the DNA to activate HRE.
Hormones That Use 2nd
Messengers
• Cannot pass through plasma membrane.
• Catecholamines, polypeptides, and
glycoproteins bind to receptor proteins on the
target cell membrane.
• Actions are mediated by 2nd messengers
(signal-transduction mechanisms).
– Extracellular hormones are transduced into
intracellular second messengers.
Hormones That Use 2nd
Messengers
2nd messenger systems:
• Adenylate cyclase
• Phospholipase C
• Tyrosine kinase
• NO
• various kinases
Adenylate Cyclase-cAMP
• Hormone binds to receptor protein.
• Dissociation of a subunit of G-protein.
• G-protein binds and activates adenylate
cyclase.
• ATP
cAMP + PPi
• cAMP attaches to inhibitory subunit of
protein kinase.
Adenylate Cyclase-cAMP
• Activates protein kinase.
• Phosphorylates enzymes within the cell to produce
hormone’s effects.
• Modulates activity of enzymes present in the cell.
• Alters metabolism of the cell.
• cAMP inactivated by phosphodiesterase.
– Hydrolyzes cAMP to inactive fragments.
Catecholamines
ACTH
FSH
LH
TSH
Glucagon
PTH
Calcitonin
++
Phospholipase-C-Ca
• Binding of epinephrine to alpha-adrenergic
receptor activates a G-protein, (phospholipase C).
• Phospholipase C splits phospholipid into inositol
triphosphate (IP3) and diacylglycerol (DAG).
• Both derivatives serve as second messengers.
++
Phospholipase-C-Ca
• IP3 diffuses through cytoplasm to ER.
• Binding of IP3 to receptor protein in ER causes Ca++
channels to open.
• Ca++ diffuses into the cytoplasm.
• Ca++ binds to calmodulin.
• Calmodulin activates specific protein kinase enzymes.
• Alters the metabolism of the cell, producing the
hormone’s effects.
Catecholamines
TRH
LHRH
Oxytocin
ADH
Two ways to increase cytosol free Ca 2+
1)By release of
Ca2+ from
intracellular
Calcium
storages
2)By influx of
Calcium from
cell exterior
Ca2+ channel
Tyrosine Kinase
• Receptor protein on cell membrane is tyrosine kinase.
• Insulin receptor consists of 2 units that dimerize when
they bind with insulin.
• Insulin binds to ligand–binding site, activating
enzymatic site.
• Autophosphorylation occurs, increasing tyrosine kinase.
• Activates signaling molecules, altering the metabolism
of the cell.
GH/PRL signaling mechanism
PRLR alpha
PRL
Extra-cellular
PRL
PRL
D1
D2
Intra-cellular
Stat
P
P
R
L
Circulation
P
R
L
D1
D2
JAK2
P
R
L
P
R
L
JAK2
P
Box1 Box1
P
P
P
Y
Y
Y
Y
Y
Y
Y
Y
P
P
P
Legend
Stat 1
Kinase
Stat 3
Stat 5
Signal Molecule
PI3K
Fyn
Src
MAPK
Known
Not Sure
Biological
Response
AKT
?
AKT
ERK
OVERVIEW
Physiological Effects of Hormones
1. Reproduction (Gonads)
2. Stress & Steroids (Adrenal)
3. Metabolism (Pancreas and Thyroid)
4. Electrolyte/Water Balance
Gonads and Placenta
• Gonads (testes and ovaries):
– Secrete sex hormones.
• Testosterone.
• Estradiol.
• Progesterone.
• Placenta:
– Secretes large amounts of estrogen and progesterone.
Sertoli cells: synthesis
androgen-binding protein and
inhibin.
Leydig cells: produce and
secrete testosterone
Testosterone: key hormone
for produce sperm, develop
male sex characters, protein
synthesis and general growth
s
Cell type
Ploidy/Chro
mosomes
#N
Oogonium diploid/46
2N
primary
Oocyte
diploid/46
4N
secondary
Oocyte
haploid/23
2N
Ovum
1N
haploid/23
Process
Oocytogenesis
(mitosis)
Time of
completion
third trimester
Dictyate in
Meiosis I
prophase I until
(Folliculogenesis) ovulation
Halted in
metaphase II
until
Meiosis II
fertilization
1. hypothalamic
GnRH control of
FSH / LH release,
2. ovarian follicular
development to
ovulation and
subsequent corpus
luteum formation
3. the feedback
control of FSH / LH
secretion by ovarian
hormones.
•the corpus luteum
regresses,
•there is a rapid fall in
the secretion of
oestrogen and
progesterone,
•the endometrium
undergoes shrinkage
due to extracellular
fluid loss,
•the spiral arteries
constrict,
•the endometrial blood
flow decreases with cell
death and destruction of
blood vessels `
Adrenal Glands
• Paired organs that cap the kidneys.
• Each gland consists of an outer cortex and inner
medulla.
• Adrenal medulla:
– Derived from embryonic neural crest ectoderm
(sympathetic ganglia).
– Synthesizes and secretes:
• Catecholamines (mainly epinephrine but some
norepinephrine).
Adrenal Medulla
• Innervated by sympathetic nerve fibers.
– Increase respiratory rate.
– Increase heart rate, cardiac output; and
vasoconstrict blood vessels, thus increasing
venous return.
– Stimulate glycogenolysis.
– Stimulate lipolysis.
Adrenal Glands
• Adrenal cortex:
– Does not receive neural innervation.
– Must be stimulated hormonally.
– Consists of 3 zones:
• Zona glomerulosa:
– Aldosterone: regulate Na+ and K+ balance.
• Zona fasciculata:
– Cortisol: regulate glucose metabolism.
• Zona reticularis:
– Androstenedione and DHEA: supplement sex steroids.
Pancreas
• Endocrine portion consists of islets of Langerhans.
• Alpha cells secrete glucagon.
– Stimulus is decrease in plasma glucose concentrations.
– Stimulates lipolysis.
• Beta cells secrete insulin.
– Stimulus is increase in plasma glucose concentrations.
– Promotes entry of glucose into cells.
Regulating Blood Glucose
Two major hormones:
1) insulin
2) glucagon
Origin:b cells, a cells-islet of Langerhans
Control: BG high--insulin,
BG low--glucagon
Diabetes Mellitus
Two types:
1) Type I (IDDM)
--severe, insulin dependant, juvenile onset,
--loss of beta cell mass
2) Type II (NIDDM)
--less severe, non-insulin-dependant, adult
onset, more common
--defective insulin receptors
untreatedfat metabolism(ketones) ketoacidosis
ketoacidosis
Thyroid Hormones
• Thyroid gland located just below the larynx.
• Thyroid is the largest of the pure endocrine
glands.
• Follicular cells secrete thyroxine.
• Parafollicular cells secrete calcitonin.
Production of Thyroid Hormones
• I- (iodide) actively transported into the follicle and
secreted into the colloid.
• Oxidized to (Io) iodine.
• Iodine attached to tyrosine.
– Attachment of 1 iodine produces monoiodotyrosine
(MIT).
– Attachment of 2 iodines produces diiodotyrosine
(DIT).
• MIT and DIT or 2 DIT molecules coupled.
Production of Thyroid Hormones
• T3 and T4 produced.
• TSH stimulates pinocytosis into the
follicular cell.
– Enzymes hydrolyze to T3 and T4 from
thyroglobulin.
• Attached to thyroid-binding protein and
released into blood.
T3 Effects
• Stimulates cellular respiration by:
– Production of uncoupling proteins.
– Stimulate active transport Na+/ K+ pumps.
– Lower cellular [ATP].
• Increases metabolic heat.
• Increases metabolic rate.
– Stimulates increased consumption of glucose,
fatty acids and other molecules.
Hormonal Regulation: H2O, Electrolytes
Major organs: kidney, intestine, and bone
Antidiuretic hormone (ADH): also vasopressin,
regulates H2O turnover in kidney
--  premeability of H2O in duct ( urine)
Aldosterone:  Na+ reabsorption,  blood
osmolarity
Atrial natriuretic peptide (ANP):  Na+ , ( urine)