Mechanism of Hormone Action

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Mechanism of Hormone Action
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Hormone Receptors

• All hormones act through receptors
• Cells that contain receptors are targets

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Hormone Receptors

• Hormones regulate specific target tissues.
• How are target tissues selected by specific
  hormones?
• Determined through receptors on target cells that
  provide the specificity for hormone-cell
  interactions
• Receptors may be located in the cell membrane,
  cytoplasm, or nucleus.

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Principles of Receptor Binding

• 1) Hormone specificity
• Receptors interact with (bind) specific hormones
• Hormones have a primary receptor, but may
  interact with less affinity with other receptors.
  Examples
• Progesterone will bind androgen receptors
• Aldosterone will bind glucocorticoid receptors
• Testosterone will bind estrogen and progestin
  receptors
• 2) High affinity
• Receptor affinity is related to concentration of
  hormone.

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Principles of Receptor Binding

• 3) Tissue Specificity
• Target tissues containing receptors respond
  specifically to the hormone (ligand) that binds
  the receptor. (At physiological concentrations)
• Some non-specific binding may occur to other
  tissues, but this binding is of low affinity with
  no hormonal or tissue specificity.

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Principles of Receptor Binding

• 4) Saturable
• Usually one specific binding site per molecule
• Should be a finite number of receptors
• 5) Reversibility
• Hormone binding must be reversible.
• The on/off rate is dependent on binding
  affinity

H R HR Effect
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Number of Receptors

• Number of receptors is not static.
• Numbers change with physiological conditions
  development, differentiation, stimulation or
  inhibition.

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Number of Receptors

• Hormones regulate their own or other hormone
  receptors.
• Prolactin induces appearance of prolactin
  receptors (up regulation)
• Prolactin induces appearance of estrogen
  receptors (results in synergy)
• Chronic exposure of cells to insulin results in
  decreased binding (down regulation) of the
  insulin receptor.

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Number of Receptors

• Down regulation of receptors

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Plasma Membrane Receptors

• Receptors bind water soluble hormones and
  transduce the signal
• Some membrane receptors are enzymes
• Some membrane receptors are coupled to G
  (GTP-binding) proteins
• Receptor Structure transmembrane protein

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Plasma Membrane Receptors

• Spare receptors on the cell surface
• Usually more receptors on the plasma membrane
  than needed for maximal response
• Maximal biological responses is achieved when
  only a small percentage of receptors are occupied
  
• Excess receptor number increases sensitivity of
  the cell to low levels of hormone
• Maximal stimulation of steroidogenesis by Leydig
  cells occurs when only 1 of LH receptors are
  occupied
• Full steroid-induced transcriptional response may
  only require 10 receptors

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Plasma Membrane Receptors

• More than one hormone can activate the same
  intracellular signal transduction
• Example Several hormones can activate cAMP in
  the same cell

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Receptors that Activate G Proteins

• Rall Sutherland studied epinephrine (epi)
  induced secretion of glucose from liver cells
• Found ? in cAMP after epi treatment
• Identified adenylyl (adenylate) cyclase
• Orly Schramm demonstrated that epi receptor and
  AC were separate molecules
• Fused adrenal tumor cells (active AC) with turkey
  RBC (functional receptor)

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Synthesis and Breakdown of cAMP
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Adenylyl Cyclase
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Receptors that Activate G Proteins

• Rodbell Gilman et al. isolated and showed the
  presence of a "Guanine nucleotide binding
  protein" (a.k.a., G protein) that mediated the
  effect of epi on AC

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Role of G Proteins
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Activation of Protein Kinase A

• cAMP activates Protein Kinase A (PKA)
• PKA phosphorylates various proteins in the cell
  (ATP is PO4 donor)
• PO4 put on OH groups of threonine serine of
  proteins (changes their shape)
• Phosphorylation can either activate or inactivate
  proteins (bc of change in shape)

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What Turns the cAMP System Off?

• G? protein has inherent GTPase activity
• Phosphodiesterase enzyme breaks down cAMP ? AMP
• Phosphatase enzymes remove PO4 groups from
  proteins
• Hormone/Receptor complex dissociates (or becomes
  down-regulated )

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Phosphatidylinositol/Phospholipase C System
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Signal Transduction Leads to Cascade of Activity

• Proteins Regulated by Phosphorylation
• Kinases transfers PO4 onto proteins
• Enzymes regulate metabolism
• Transcription factors regulate gene activity

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The Proteins Phosphorylated by PKA Depends on
Cell Type

• Different cell types contain different proteins
  (enzymes)
• Therefore, PKA activates different pathways in
  different cells
• Example
• PKA stimulates glycogen bkdn in liver
• PKA stimulates lipid bkdn in adipose tissue

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Different signal molecules can initiate the same
response

• Example Epinephrine and glucagon both initiate
  glycogen breakdown

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