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Lecture #27
Lecturer A. N. Koval
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Koval A. (C), 2011 2 10.04.2014
Hormones Transduce Signals to
Affect Homeostatic Mechanisms
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Koval A. (C), 2011 3 10.04.2014
Lipophilic hormones
Classifying hormones into hydrophilic and
lipophilic molecules indicates the chemical
properties of the two groups of hormones
and also reflects differences in their mode
of action.
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Mechanism of Action of Lipophilic
Hormones
Koval A. (C), 2011 4 10.04.2014
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Receptors of Lipophilic Hormones
Koval A. (C), 2011 5 10.04.2014
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Koval A. (C), 2011 6 10.04.2014
Regulation of gene expression by
class I hormones Steroid hormones
readily gain access to the cytoplasmic compartment of target cells.
Glucocorticoid hormones (solid triangles) encounter their cognate receptor in the cytoplasm, where it exists in a complex with heat shock protein 90 (hsp).
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Koval A. (C), 2011 7 10.04.2014
Cytokines Cytokines are
growth factors
that specifically
act to orchestrate
the development
of hemopoietic
cells and the
immune response
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Members of one of the
cytokine receptor
superfamilies, showing
shared structural elements
Koval A. (C), 2011 8 10.04.2014
All the subunits except the
subunit in subfamily 3 have
four conserved cysteine
residues (open boxes at
top) and a Trp-Ser-X-Trp-
Ser motif (pink).
Many subunits also contain
a critical regulatory domain
in their cytoplasmic portions
(green). CNTF, ciliary neurotrophic factor;
LIF, leukemia inhibitory factor;
OSM, oncostatin M;
PRL, prolactin.
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Koval A. (C), 2011 9 10.04.2014
Signal Transduction in the Cytokines
As peptides or
proteins, the
cytokines are
hydrophilic signaling
substances that act
by binding to
receptors on the cell
surface.
Binding of a cytokine
to its receptor leads
via several
intermediate steps to
the activation of
transcription of
specific genes.
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Koval A. (C), 2011 10 10.04.2014
Regulation of the NF-kB pathway NF-kB consists of two subunits, p50 and p65.
important for the inflammatory response.
NF-kB is restricted from entering the nucleus by IkB, an inhibitor of NF-kB.
This cytoplasmic protein is phosphorylated by an IKK complex which is activated by cytokines, reactive oxygen species, and mitogens.
IkB can be degraded, thus releasing its hold on NF-kB.
Glucocorticoids, potent antiinflammatory agents, can affect this process.
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Mechanism of Action of Hormones
Koval A. (C), 2011 13 10.04.2014
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Signal Transduction by G-proteins
Koval A. (C), 2011 14 10.04.2014
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Koval A. (C), 2011 15 10.04.2014
Insulin Stucture
Koolman, 2005
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Koval A. (C), 2011 16 10.04.2014
Insulin (Monomer)
Koolman, 2005
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Koval A. (C), 2011 17 10.04.2014
Insulin biosynthesis
Koolman, 2005
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Koval A. (C), 2011 18 10.04.2014
Insulin signaling pathways
IGFBP , insulin-like growth factor binding protein;
IRS 1–4, insulin receptor substrate isoforms 1–4;
PI-3 kinase, phosphatidylinositol 3-kinase;
PTEN, phosphatase and tensin homolog deleted on chromosome 10;
PKB, protein kinase B;
SGK, serum and glucocorticoid-regulated kinase;
aPKC, atypical protein kinase C;
p70S6K, p70 ribosomal protein S6 kinase;
mTOR, mammalian target of rapamycin;
GRB2, growth factor receptor binding protein 2;
mSOS, mammalian son of sevenless;
MEK, MAP kinase kinase and ERK kinase;
MAP kinase, mitogen-activated protein kinase
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Koval A. (C), 2011 19 10.04.2014
Effects of
Insulin
Deficiency
Hyperglycemia glucosuria
Hyperlipidemia atherosclerosis
Metabolic acidosis Ketosis
Diabetic coma
Hyperosmolarity of blood Koolman, 2005
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Thyroid Hormone Biochemistry
The thyroid hormones may be considered the
accelerator pedal of metabolism.
T3 and T4 increase the metabolic rate of
tissues and affect the basal metabolic
rate.
• Altered transcription after the
binding of T3 to its nuclear receptor.
• ↑ thermogenesis, mitochondrial
oxidative metabolism,
• ATP utilization, Na+/K+-ATPase.
• Lipolysis is stimulated by cAMP-
dependent activation of hormone
sensitive lipase => fatty acids
oxidized => ATP used for
thermogenesis.
Koval A. (C), 2011 20 10.04.2014
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Effects of Thyroid Hormones
There are 3 groups of the effects:
1. Anabolic action - influence on growth
and differentiation of tissues.
2. Metabolic effects – increase of catabolic processes
intensity (oxidation, lipolysis).
3. Sensibilizing effects – increase of cell sensitivity
to action of other hormones, in
particular estrogens and catecholamines.
Koval A. (C), 2011 21 10.04.2014
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Sensibilizing and Permissive
Effect of Hormones
Sensibilizing effect – when one hormone
increases the effect of the others.
Permissive effect – when there is no effect
of other hormones in the absence of one
hormone.
Koval A. (C), 2011 22 10.04.2014
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Catabolism of Catecholamines
Koval A. (C), 2011 23 10.04.2014
MAO – monoamine oxidase
COMT – catechol-O-methyl
transferase
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Koval A. (C), 2011 24 10.04.2014
Biosynthesis
of Steroid
Hormones
All steroid hormones derived from cholesterol.
Hydroxylase reactions are catalyzed by monooxygenases (“hydroxylases”), cytochrome P450 family.
Estrogens posess specific aromatic A ring as a result of aromatase action.
Pregnenolone as important intermediate. Also progesterone.
Koolman, 2005
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Koval A. (C), 2011 25 10.04.2014
Inactivation of Steroid Hormones
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10.04.2014 Koval (C), 2008 26