Quick Review of Feedback Systems

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Hormone Survey:
Getting to Know Your Hormones
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Classification of Hormones
Classification by System/Function
Classification by Source
Classification by Structure
- Peptide Hormones
-Steroid Hormones
-Amino Acid Derivatives
Classification of Hormone Receptors
Some Things to Know about a Hormone
• Source (what organ/cell produces and/or
secretes it?)
• What is its target cell(s)?
• What is the effect on target cells?
• What regulates its production/secretion?
• What type of chemical structure?
• Details of transport/metabolism?
• What type of receptor/signal transduction?
Learning Objectives: Classification of
Hormones by Function



Describe the various functions that the
endocrine system regulates.
Become familiar with the range of hormones
involved in these functions.
You are NOT responsible for specific names
of these hormones yet.
Classification of Hormones by
Function
• Reproductive Hormones:
- estrogens (estradiol), androgens (testosterone),
progesterone
- luteinizing hormone, follicle-stimulating hormone,
prolactin, oxytocin
- inhibin, activin, follistatin
- gonadotropin-releasing hormone
Classification of Hormones by
Function
• Growth Hormones:
- Growth hormone (somatotropin)
- somatomedins (insulin-like growth factors)
- somatostatin, growth hormone-releasing
hormone
- nerve growth factor, epidermal growth factor,
fibroblast growth factor, etc.
Classification of Hormones by
Function
• Hormones regulating carbohydrate/energy
metabolism:
Insulin, glucagon, cortisol, growth hormone,
epinephrine
• Hormones regulating general body metabolism: thyroid hormone (T3, T4)
- thyroid stimulating hormone (TSH, or thyrotropin)
- thyrotropin-releasing hormone (TRH)
Classification of Hormones by
Function
• Hormones involved in stress responses:
- norepinephrine, epinephrine
- cortisol
• Hormones involved in mineral and water balance:
- aldosterone, renin, vasopressin
- atrial natriuretic peptide
Classification of Hormones by
Function
• Regulation of Calcium Metabolism:
parathyroid hormone, calcitonin, vitamin D, others….
• Regulation of Digestion
cholecystokinin, gastrin, secretin, somatostatin
• Regulation of Blood Formation:
erythropoietin, erythrocyte differentiation factor
Classification of Hormones by
Source
• Hypothalamus (brain): acts on the pituitary to
control the release of pituitary hormones:
-gonadotropin-releasing hormone (GnRH)
-thyrotropin-releasing hormone (TRH)
-corticotropin-releasing hormone (CRH)
-prolactin-inhibiting factor (probably dopamine?)
-somatostatin
-growth hormone-releasing hormone (GHRH)
Classification of Hormones by
Source
• Anterior Pituitary (anterior lobe):
- luteinizing hormone (LH)
- follicle-stimulating hormone (FSH)
- thyroid-stimulating hormone (TSH)
- growth hormone (GH; or somatotropin)
- prolactin (PRL)
- adrenal corticotropic hormone (ACTH, or
corticotropin)
Classification of Hormones by
Source
• Posterior Pituitary (posterior lobe):
- oxytocin
- vasopressin (antidiuretic hormone, ADH)
• Intermediate Lobe (absent in adult human):
- melanocyte-stimulating hormone
Classification of Hormones by
Source
• Thyroid gland:
- thyroid hormones (T3, T4)
- calcitonin
• Parathyroid gland:
- parathyroid hormone
Classification of Hormones by
Source
• Ovary and testis:
- estrogens, androgens, progesterone
- inhibins, activins, follistatin
- relaxin

Placenta:
- human chorionic gonadotropin (hCG)
- placental lactogen
- steroid hormone
Classification of Hormones by
Source
• Adrenal cortex:
- glucocorticoids (cortisol, corticosterone)
- mineralocorticoids (aldosterone)
- androgens (androstenedione)
• Adrenal medulla:
- epinephrine, norepinephrine
Classification of Hormones by
Source
• Pancreas (endocrine):
- insulin
- glucagon
• Kidney:
- erythropoietin
• GI Tract:
- gastrin
- cholecystokinin
- secretin
- somatostatin
• Heart:
- atrial natriuretic peptide
Reminder….
• At this point, do NOT memorize the preceding
lists of hormone sources and functions.
• DO understand the following information on
hormone structure….
Classification by Structure
• Hormones can be classified based on their
structure as steroid hormones, peptide
hormones, or amino acid derivatives.
• The structure of the hormone determines:
– How it is made (gene product; cholesterol
derivative; amino acid derivative)
– How it is transported (binding protein?)
– How it interacts with receptors on target cells
(hormone-receptor interactions)
Hormone-Receptor Interactions
• Hormones and receptors bind due to noncovalent
bonding between them.
• This also involves a three-dimensional “lock and key”
conformation
BUT, there is a caveat – this analogy breaks down:
Receptor Affinity
Receptor Number
Hormone-Receptor Interactions
• Only specific regions of the hormone and receptor
interact.
– Some regions determine hormone binding
– Other regions allow signal transduction
• Small changes in hormone or receptor structure can
prevent hormone binding and/or hormone activity
Peptide Hormones: Water Soluble
Gene Products
Recall that proteins are gene products:
gene (DNA)
transcription
mRNA
translation
protein
Structure of Peptide Hormones
• Proteins are made up of amino acids, connected to
each other by peptide bonds.
• Peptide hormones may be very short (three amino
acids) to very long (over one hundred amino acids)
in length.
• They typically have an amino terminus (NH2) and a
carboxyl terminus (-COOH).
NH2
COOH
Structure of Peptide Hormones
• Peptides have primary, secondary, tertiary, and
quaternary structure:
Peptide Hormones: Subunit Structure
• Peptide hormones may consist of two subunits joined
together, usually by disulfide bonds at cysteine residues.
Example: LH, FSH and TSH are composed of a common alpha
subunit, and distinct beta subunits:
a
LHb
FSHb
TSHb
LH
FSH
TSH
Peptide Hormones
• The shape of peptide hormones may be influenced
by and strengthened by disulfide bridges.
• Peptides may also form ring structures, such as
oxytocin.
Peptide Hormones: Glycosylation
• Peptide hormones may be glycosylated (have
carbohydrate side chains).
• This glycosylation can affect:
- assembly of hormone subunits
- secretion from the endocrine cell
- clearance of the hormone from the circulation
- biological activity (receptor binding and
biological response of the target cell)
Peptide Hormones: Species
Homology
• The primary amino acid sequence of peptide
hormones may differ slightly from species to
species. Hormones obtained from one species
may not necessarily interact with receptors for
hormones of a different species.
Example: The human FSH receptor does not
respond well to FSH from other species.
Endocrine Bioinformatics
• Bioinformatics: The utilization of information (ie,
databases) to solve biological problems.
• Example: Suppose you were studying the hormone
prolactin, and wanted to see what chromosome it
was located on, and if there were any undiscovered
hormones which were similar in structure.
• Approach: Compare the human prolactin sequence
to the human genome database at
http://www.ncbi.nlm.nih.gov/genome/seq/HsBlast.html
Actions of Peptide Hormones
• The effects of peptide hormones are relatively quick,
but short-lived.
- Anderson et al., 2001
Half-life of Peptide Hormones
• The half-life of peptide hormones in the circulation is
relatively short (water soluble, no binding proteins).
- Fares et al., 1992
Steroid Hormones
• Steroid hormones are NOT made up of amino
acids. They have a characteristic four ring
structure, derived from cholesterol:
Examples: estrogens, androgens, progesterone, cortisol,
aldosterone
Characteristics of Steroid Hormones
• Steroid hormones are not glycosylated.
• The structure of steroid hormones is the same in
all species (estradiol in rats is the same as
estradiol in humans).
• Is there a gene for testosterone? How is
testosterone made? How is its production
regulated?
Characteristics of Steroid Hormones
• Steroid hormones have more gradual and longlasting effects than peptide hormones (in general).
Characteristics of Steroid Hormones
• Steroid hormones have a relatively longer half life in
the circulation (in general, compared with peptide
hormones); reflects plasma binding proteins.
Amino Acid Derivatives (Amines)
• There are other hormones which are not
steroids and not peptides, but are derived
from amino acid precursors.
• Epinephrine (adrenaline): Derived from
tyrosine.
Amino Acid Derivatives
• Thyroid hormones (triiodothyronine, thyroxine);
are also produced from tyrosine.
• In this case, get lipid soluble hormones (not
water soluble)
Water soluble
hormones
gene
Lipid soluble
hormones
synthesis
amino acid
mRNA
derivatives
(epinephrine,
peptide hormones norepinephrine)
synthesis
stimulus
cholesterol
steroid hormone
secretion
amino acid
derivative
(thyroid
hormone)
storage
diffusion
secretion
free hormone
free hormone
binding protein
Hormone
Level
Hormone
Level
Time
Time
plasma membrane
receptors
ion flux
second
messengers
(cAMP,
cGMP)
target
DNA
phosphorylation
mRNA
protein
cellular response
cellular response
Types of receptors
 Receptors for the water soluble hormones are found
on the surface of the target cell, on the plasma
membrane.
 These types of receptors are coupled to various second
messenger systems which mediate the action of the
hormone in the target cell.
 Receptors for the lipid soluble hormones reside in
the nucleus (and sometimes the cytoplasm) of the
target cell.
 Because these hormones can diffuse through the lipid
bilayer of the plasma membrane, their receptors are
located on the interior of the target cell
Hormones and their receptors
Hormone
Class of hormone
Location
Amine (epinephrine)
Water-soluble
Cell surface
Amine (thyroid
hormone)
Lipid soluble
Intracellular
Peptide/protein
Water soluble
Cell surface
Steroids and Vitamin
D
Lipid Soluble
Intracellular
Second messenger systems
Receptors for the water soluble hormones are
found on the surface of the target cell, on the
plasma membrane. These types of receptors
are coupled to various second messenger
systems which mediate the action of the
hormone in the target cell
Second messengers for cellsurface receptors
 Second messenger systems include:
 Adenylate cyclase which catalyzes the conversion of ATP to
cyclic AMP;
 Guanylate cyclase which catalyzes the conversion of GMP
to cyclic GMP (cyclic AMP and cyclic GMP are known
collectively as cyclic nucleotides);
 Calcium and calmodulin; phospholipase C which catalyzes
phosphoinositide turnover producing inositol phosphates
and diacyl glycerol.
Types of receptors
Second messenger systems
 Each of these second messenger systems activates a
specific protein kinase enzyme.
 These include cyclic nucleotide-dependent protein kinases
 Calcium/calmodulin-dependent protein kinase, and
protein kinase C which depends on diacyl glycerol binding
for activation.
 Protein kinase C activity is further increased by calcium which is
released by the action of inositol phosphates.
Second messenger systems
 The generation of second messengers and activation
of specific protein kinases results in changes in the
activity of the target cell which characterizes the
response that the hormone evokes.
 Changes evoked by the actions of second messengers
are usually rapid
Signal transduction mechanisms
of hormones
Activation of
adenylate
cyclase
Inhibition of
adenylate
cyclase
Increased
phosphoinositide
turnover
Tyrosine
kinase
activation
b-adrenergic
a2-adrenergic
a1-adgrenergic
Insulin
LH, FSH, TSH,
hCG
Opioid
Angiotensin II
Growth factors
(PDGF, EGF,
FGF, IGF-1
Glucagon
Muscarinic
cholinergic –
M2
Muscarinic
cholinergic –
M3
Vasopressin –
V1
Growth
hormone
VasopressinV2
ACTH
Prolactin
Cell surface receptor action
G-protein coupled receptors
Adenylate cyclase, cAMP and PKA
Amplification
via 2nd
messenger
Transmembrane kinase-linked
receptors
 Certain receptors have intrinsic kinase activity. These
include receptors for growth factors, insulin etc.
Receptors for growth factors usually have intrinsic tyrosine
kinase activity
 Other tyrosine-kinase associated receptor, such as those
for Growth Hormone, Prolactin and the cytokines, do not
have intrinsic kinase activity, but activate soluble,
intracellular kinases such as the Jak kinases.
 In addition, a newly described class of receptors have
intrinsic serine/threonine kinase activity—this class
includes receptors for inhibin, activin, TGFb, and Mullerian
Inhibitory Factor (MIF).
Protein tyrosine kinase receptors
Receptors for lipid-soluble
hormones reside within the cell
 Because these hormones can diffuse through the lipid bilayer
of the plasma membrane, their receptors are located on the
interior of the target cell.
 The lipid soluble hormone diffuses into the cell and binds to
the receptor which undergoes a conformational change. The
receptor-hormone complex is then binds to specific DNA
sequences called response elements.
 These DNA sequences are in the regulatory regions of genes.
Receptors for lipid-soluble
hormones reside within the cell
 The receptor-hormone complex binds to the regulatory region
of the gene and changes the expression of that gene.
 In most cases binding of receptor-hormone complex to the
gene stimulating the transcription of messenger RNA.
 The messenger RNA travels to the cytoplasm where it is
translated into protein. The translated proteins that are
produced participate in the response that is evoked by the
hormone in the target cell
 Responses evoked by lipid soluble hormones are usually
SLOW, requiring transcription/translation to evoke
physiological responses.
Mechanism of lipid
soluble hormone
action
Receptor control mechanisms
• Hormonally induced negative regulation of receptors is
referred to as homologous-desensitization
• This homeostatic mechanism protects from toxic effects of
hormone excess.
• Heterologous desensitization occurs when exposure of the cell
to one agonist reduces the responsiveness of the cell any
other agonist that acts through a different receptor.
• This most commonly occurs through receptors that act
through the adenylyl cyclase system.
• Heterologous desensitization results in a broad pattern of
refractoriness with slower onset than homologous
desensitization
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