Categories of Chemical Messengers
Intracrine
Endocrine
Autocrine
Ectocrine
Paracrine
Endocrinology: study of hormones
General Features of the endocrine system:
Transport
Gland
Hormone
Target Cell
rich blood supply
secreted into the blood
ductless
can reach virtually every cell in the body
hormone receptors
are very specific
Endocrinology: study of hormones
Transport
Gland
Hormones
Functional
classification
Structural
classification
Target Cell
Hormones:
functional classification
• Metabolism (i.e.: nutrient breakdown and absorbtion, and
anabolic and catabolic metabolism)
• Reproductive function
• Growth and metamorphosis
• Osmoregulation and excretion of water and salts
• Synthesis and release of other hormones
• Permissive actions
• Stimulate muscle contraction (especially smooth muscle
in the gut and genital tract)
• Activational and/or Organizational effects on behavior
Organizational vs. Activational
Example: Sexual behavior
Mounting behavior
lordosis
Hormones:
functional classification
• Metabolism (i.e.: nutrient breakdown and absorbtion, and
anabolic and catabolic metabolism)
• Reproductive function
• Growth and metamorphosis
• Osmoregulation and excretion of water and salts
• Synthesis and release of other hormones
• Permissive actions
• Stimulate muscle contraction (especially smooth muscle
in the gut and genital tract)
• Activational and/or Organizational effects on behavior
• Facultative Actions
Ham Creek,
Hudson Valley
Hormones:
structural classification
• Helps us understand how hormones are:
– Synthesized
– Secreted
– Transported
– Have effects at the Target Cell
• To start: what are the 4 major groups of
organic compounds?
• Biochem majors?.....
Hormones:
structural classification
• Peptide Hormones
– Made up of amino acid building blocks
• 3 to <180 amino acids in length
– Soluble in water?
• Yes
– Synthesis
GnRH
pGLU – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
CELL
Synthesis and
secretion of a
peptide
hormone
NUCLEUS
DNA
TRANSCRIPTION
RNA PROCESSING
RNA TRANSPORT
releasing
hormone
mRNA
mRNA TRANSLATION
PROTEIN SYNTHESIS
Peptide hormone secretion can be:
1) constitutive
2) regulated
MEMBRANE
PROTEIN
PROCESSING
PACKAGED IN A
SECRETORY VESICLE
SECRETION BY
EXOCYTOSIS
Hormones:
structural classification
• STEROIDS
– All steroids are made from cholesterol
– Water soluble?
• NO
• Almost all have binding proteins for transport in blood
• They can pass across membranes
– No storage
– Receptors are intracellular
– Synthesis
CELL
Synthesis and
secretion of a
Steroid
hormone
NUCLEUS
Protein synthesis for:
-Cell growth
-cell division
-Enzymes for mitochondria
Mitochondria
It also may occur in the
endoplasmic reticulum
enzymes
stimulating
hormone
Cholesterol
CH
3
C-CH
2-C5H11
steroid
HO
Steroid hormone secretion must be:
constitutive
It cannot be regulated
Cholesterol store in cell
MEMBRANE
SECRETION
Steroid Biosynthesis
• All steroids start from
cholesterol
• Each arrow is one enzymatic
step
• Synthesis of a certain steroid
will only occur if the
appropriate enzymes are
present
Hormones:
structural classification
• Monoamines
– Epinephrine, norepinephrine and dopamine
• All derived from a single amino acid: tyrosine
– Melatonin and serotonin
• Derived from the amino acid tryptophan
OH
OH
– Synthesis:
H
O
C
H
H
C
H
H
N
CH3
epinephrine
• Enzymes present in cell alter the amino acid
Hormones:
structural classification
• Thyroid hormones
– Modified from amino acid tyrosine
• Iodine is incorporated (think salt)
– Two forms: thyroxine (T4 = four iodines) and
tri-iodothyronine (T3 = three iodines)
– Soluble in water?
• No
– Synthesis
I
Synthesis of thyroid hormones
stimulating
hormone
I
I
vessicle
Cell
membrane
I
OH
I
I
OH
OH
CH2
CH2
I
I
OH
I
I
OH
I
I
O
lysozyme
I
enzymes
I
CH2
I
CH2
CH2
OH
thyroglobulin
I
I
OH
I
O
I
Golgi apparatus
I
I
CH2
O
I
I
I
CH2
cytoplasm
Hormones:
structural classification
• EICOSANOIDS
– Lipid hormones
– All are derived from arachidonic acid (a fatty acid)
• Prostaglandins-stimulate smooth muscle, induce
inflammation and fever
– Aspirin inhibits prostaglandin synthesis
• Leukotrienes-contribute to inflammatory and allergic
responses
• Thromboxanes-facilitates clotting of blood platelets
OH
COOH
PROSTAGLANDIN
– Synthesis
PGF2alpha
OH
OH
• Arachidonic acid is synthesized from diacyl glycerol (DAG)
Regulation of Hormone Levels
How does the body recognize
and regulate how much hormone
is present in the blood?
Negative Feedback
simple
HYPOTHALAMUS
-
CRH
PITUITARY
ACTH
ADRENALS
-
= negative feedback
Glucocorticoids
(i.e. cortisol)
Negative Feedback
-
HYPOTHALAMUS
-
GnRH
PITUITARY
-
LH
TESTIS
Testosterone
-
= negative feedback
Negative Feedback
• A process where increasing hormone levels
serve to shut down releasing and stimulating
hormones ‘upstream’
• set-point level can be changed depending on
season, parental care, environmental conditions,
etc.
Positive Feedback
• A process where increasing hormone
levels stimulate further secretion of
releasing and stimulating hormones
Endocrinology: study of hormones
Transport
Gland
Hormone
Target Cell
Binding Proteins
• 3 Important concepts
• Binding globulin characteristics
capacity and affinity
two examples
• Other binding proteins
STRESSOR
Central Nervous System
hypothalamus
Corticosteroid Binding Globulin
CRH
pituitary
ACTH
adrenals
Glucocorticoids
(cortisol, corticosterone)
Target Tissue
Transport
• Binding proteins:
– carry hormones in the blood
• Important concepts
– Bound vs. Free: In the blood there is hormone bound
to binding globulin, and hormone that is free
– Only free hormone can exit the blood stream
• only free reaches tissue to bind receptors
• only free can be broken down in the liver
– ↑ binding protein = ↑ hormone bound, ? free hormone
• ↑ binding protein = ↑ hormone bound, ↓ free hormone
• So, binding proteins can regulate
– Bioavailability
– Clearance rates
Characteristics of Binding Proteins
• Affinity
– how well hormone binds to binding globulin
• tightly bound = high affinity
• loosely bound = low affinity
– Increase affinity…what happens to free hormone?
– Human Example
• Capacity
– total number of binding globulins present
– Decrease capacity…what happens to free hormone?
– Bird Example
White-crowned sparrows
Total CORT (ng/ml)
60
total CORT
50
40
30
20
10
0
0-3 minutes
Specific Binding (nM)
1 brood
600
500
30 minutes
CBG capacity
400
300
200
100
0
pugetensis
2-3 broods
oriantha
gambelii
Free CORT (ng/ml)
3.5
3
Free CORT
2.5
2
1.5
1
.5
1-2 broods
0
0-3 minutes
30 minutes
Transport: Binding Proteins
BINDING PROTEIN
ABBREVIATION
HORMONES BOUND
Corticosteroid-binding globulin
CBG
Sex-steroid binding globulin
SBG or SSBG
Progesterone-binding globulin
PBG
glucocorticoids and
progesterone
Testosterone and
estradiol
progesterone
Thyroxine-binding protein
TBP
Growth Hormone binding protein GH-BP
Insulin-like growth factor binding IGF-BPs
proteins
Neurophysins I and II
Corticotropin releasing
releasing factor-binding protein
CRF-BP
Thyroxine and triiodothyronine
Growth hormone
Insulin-like growth
factors I and II
Vasopressin and
oxytocin
Corticotropin
factor
Review
• Binding proteins: carry hormones in the blood
• Important concepts
-Bound vs. Free: In the blood there is hormone bound
to binding globulin, and hormone that is free
-Binding proteins regulate how much free H is available
to tissues or alter clearance rate (how much will be
broken down)
• Affinity vs. capacity
-CBG mutations in humans
-CBG altering free CORT levels: bird example
• So, binding proteins can regulate bioavailability
and clearance rate of hormones
Endocrinology: study of hormones
Glands
Transport
Hormone
Target Cell
Endocrine
Glands
The human brain
Human Brain: coronal section
Lateral ventricles
thalamus
3rd ventricle
hypothalamus
Human Brain: Sagittal Section
Mammalian Pituitary
Hypothalamus
OC
Infundibulum
THE NOSE
Posterior Pituitary
Anterior Pituitary
(neurohypophysis)
(pars nervosa)
(adenohypophysis)
(pars distalis)
Intermediate lobe
(pars intermedia)
Hypothalamus
OC
Infundibulum
THE NOSE
Posterior Pituitary
(neurohypophysis)
(pars nervosa)
Oxytocin
Vasopressin
Hypothalamus
OC
Median
Eminence
Releasing and Inhibiting
hormones are secreted
from the hypothalamus
Posterior Pituitary
Anterior Pituitary
(neurohypophysis)
(pars nervosa)
(adenohypophysis)
(pars distalis)
Intermediate lobe
(pars intermedia)
THE NOSE
Portal System
Hypothalamus
Posterior Pituitary
(pars nervosa)
Median
Eminence
Intermediate lobe
(pars intermedia)
the nose
Anterior Pituitary
(pars distalis)
Median
eminence
Hypothalamo-pituitary
blood portal system
Hypothalamoportal vessels
Pars nervosa
Pars
distalis
Hypothalamoportal vessels
Pars distalis
Median
eminence
Hypothalamus
OC
Median
Eminence
Releasing and Inhibiting
hormones are secreted
from the hypothalamus
Posterior Pituitary
Anterior Pituitary
(neurohypophysis)
(pars nervosa)
(adenohypophysis)
(pars distalis)
Intermediate lobe
(pars intermedia)
MSH
ACTH TSH
PRL LH FSH
GH
 endorphins
THE NOSE
Hypothalamus-pituitary control center
hypothalamus
Anterior pituitary
Hypothalamus
Posterior pituitary or
Pars nervosa
Median
eminence
Portal system
Anterior pituitary
Mammal hypothalamo-pituitary unit
Hypothalamus
Median
eminence
Pars intermedia
Pars nervosa
Pars distalis
HypothalamoPortal vessels
Endocrinology: study of hormones
Transport
Gland
Hormone
Target Cell
Mechanism of Action
Characteristics of Receptors
• Two major components
– Recognition site: specific for hormone
– Effector: the portion of the receptor that
changes upon hormone binding and initiates
action in the cell
Receptor as
Enzyme
G-protein coupled receptor
Ligand-gated
ion channel
+
G
+
+
+
↑↓ second messengers
Intracellular Receptor
↑↓ second messengers
nucleus
Receptor as
Enzyme
G-protein coupled receptor
Ligand-gated
ion channel
G
↑↓ second messengers
+
+
+
Intracellular Receptor
↑↓ second messengers
nucleus
Receptor as
Enzyme
G-protein coupled receptor
Ligand-gated
ion channel
G
↑↓ second messengers
+
+
+
Intracellular Receptor
↑↓ second messengers
mRNA
nucleus
G-protein-coupled Receptors
• G proteins activate enzymes
– Adenylate cyclase which produces cAMP
– Phospholipase C which produces IP3 and
DAG
• G proteins can be stimulatory (Gs) or
inhibitory (Gi)
• Once GTP returns to the inactive form
(GDP), the -subunit is no longer active,
and returns to the -subunit.
Steroid Receptors
cellular
space
Cytoplasm
Nucleus
DNA
r
90
90
r
r
r
r
r
90
90
90
Protein
Hormone-receptor binds to DNA
synthesis
RNA
mRNA
r
space
Intra-cellular space
Extra-
processing
r
Capillary
Ribosomes
hormone
90
r
Heat shock protein 90
Hormone receptor
• Steroid Receptors are transcription factors
• They usually dimerize
• Two major components:
– Ligand binding domain (recognition site)
– DNA binding domain (effector)
• Contains Zinc fingers
• Binds to DNA at Hormone Response Element
Ligand binding domain
R
R
Zinc fingers at the DNA
binding domain
DNA
Hormone Response Element (HRE)
Characteristics of Receptors
• Two major components
– Recognition site: specific for hormone
– Effector: the portion of the receptor that
changes upon hormone binding and initiates
action in the cell
• Common properties of all receptors
– Specificity
– Capacity
– Affinity
• H + R  HR
(law of mass action)
E q u ilib r iu m S a tu r a tio n B in d in g C u r v e
100% receptors bound
GR
80
[r ad io active C O R T b ou nd]
70
60
50
40
30
GR Kd = 4.0 nM
20
10
0
0 .0
2 .5
5 .0
GR
7 .5
1 0 .0
1 2 .5
1 5 .0
1 7 .5
[r ad io active C O R T in exp er im en t]
2 0 .0
(nM)
2 2 .5
2 5 .0
Equilibrium Saturation Binding Curve
80
MR
100% receptors bound
[radioactive CORT bound]
70
60
50
40
MR Kd = 0.2 nM
30
20
10
0
0.0
MR
2.5
5.0
7.5
10.0
12.5
15.0
17.5
[radioactive CORT in experiment]
20.0
(nM)
22.5
25.0
E q u ilib r iu m S a tu r a tio n B in d in g C u r v e
GR
80
MR
[r ad io active C O R T b ou nd]
70
60
50
40
MR Kd = 0.2 nM
30
GR Kd = 4.0 nM
20
10
0
0 .0
MR
2 .5
5 .0
GR
7 .5
1 0 .0
1 2 .5
1 5 .0
1 7 .5
[r ad io active C O R T in exp er im en t]
2 0 .0
(nM)
2 2 .5
2 5 .0