Hormone Survey: Getting to Know Your Hormones

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Hormone SurveyGetting to Know Your Hormones

• Classification of Hormones
• Classification by System/Function
• Classification by Source
• Classification by Structure
• - Peptide Hormones
• -Steroid Hormones
• -Amino Acid Derivatives
• Classification of Hormone Receptors

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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?

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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.

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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

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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.

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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)

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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

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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

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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)

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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)

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Classification of Hormones by Source

• Posterior Pituitary (posterior lobe)
• - oxytocin
• - vasopressin (antidiuretic hormone, ADH)
• Intermediate Lobe (absent in adult human)
• - melanocyte-stimulating hormone

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Classification of Hormones by Source

• Thyroid gland
• - thyroid hormones (T3, T4)
• - calcitonin
• Parathyroid gland
• - parathyroid hormone

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Classification of Hormones by Source

• Ovary and testis
• - estrogens, androgens, progesterone
• - inhibins, activins, follistatin
• - relaxin

• Placenta
• - human chorionic gonadotropin (hCG)
• - placental lactogen
• - steroid hormone

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Classification of Hormones by Source

• Adrenal cortex
• - glucocorticoids (cortisol, corticosterone)
• - mineralocorticoids (aldosterone)
• - androgens (androstenedione)
• Adrenal medulla
• - epinephrine, norepinephrine

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Classification of Hormones by Source

• Pancreas (endocrine)
• - insulin
• - glucagon
• Kidney
• - erythropoietin
• GI Tract
• - gastrin
• - cholecystokinin
• - secretin
• - somatostatin
• Heart
• - atrial natriuretic peptide

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Reminder.

• At this point, do NOT memorize the preceding
  lists of hormone sources and functions.
• DO understand the following information on
  hormone structure.

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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)

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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

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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

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Peptide Hormones Water Soluble Gene Products

• Recall that proteins are gene products
• gene (DNA)
• transcription
• mRNA
• translation
• protein

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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
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Structure of Peptide Hormones

• Peptides have primary, secondary, tertiary, and
  quaternary structure

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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

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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.

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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)

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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.

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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.htm
  l

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Actions of Peptide Hormones

• The effects of peptide hormones are relatively
  quick, but short-lived.

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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
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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
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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?

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Characteristics of Steroid Hormones

• Steroid hormones have more gradual and
  long-lasting effects than peptide hormones (in
  general).

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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.

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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.

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Amino Acid Derivatives

• Thyroid hormones (triiodothyronine, thyroxine)
  are also produced from tyrosine.
• In this case, get lipid soluble hormones (not
  water soluble)

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Water soluble hormones
Lipid soluble hormones
gene mRNA peptide hormones
synthesis
synthesis
stimulus
amino acid derivatives (epinephrine, norepinephrin
e)
cholesterol steroid hormone
amino acid derivative (thyroid hormone)
secretion
storage
diffusion
secretion
free hormone
free hormone
binding protein
Hormone Level
Hormone Level
Time
Time
plasma membrane receptors
ion flux
target DNA
second messengers (cAMP, cGMP)
phosphorylation
mRNA
protein
cellular response
cellular response
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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

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Hormones and their receptors
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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

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Second messengers for cell-surface 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.

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Types of receptors
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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.

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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

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Signal transduction mechanisms of hormones
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Cell surface receptor action
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G-protein coupled receptors
Adenylate cyclase, cAMP and PKA
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Amplification via 2nd messenger
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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
  activitythis class includes receptors for
  inhibin, activin, TGFb, and Mullerian Inhibitory
  Factor (MIF).

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Protein tyrosine kinase receptors
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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.

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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.

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Mechanism of lipid soluble hormone action
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Receptor control mechanisms

• Hormonally induced negative regulation of
  receptors is referred to as homologous-desensitiza
  tion
• 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