Transcript messenger 74

Introduction to
Endocrinology
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine
Coordination of Body Functions
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6)
nervous system (neurotransmitters into the
synaptic junctions – locally)
endocrine system (hormones into blood)
neuroendocrine (neurohormones into blood)
paracrines (secreted into extracellular fluid
and affect neighboring different target cells)
autocrines (affect same cells)
cytokines (peptides - 5,4 or 2 - interleukins,
lymphokines, adipokines (leptin))
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some endocrine hormones affect many
different types of cells of the body (growth
hormone, thyroxine)
other hormones affect mainly specific target
tissues (ACTH – adrenal cortex)
regulation: metabolism, growth and
development, water and electrolyte balance,
reproduction, and behavior
Chemical Structure and Synthesis
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2)
3)
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proteins and polypeptides
steroids
derivatives of the amino acid tyrosine
(thyroid and the adrenal medullae)
there are no known polysaccharides or
nucleic acid hormones
1) Protein Hormones
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widespread, water soluble
from 3 (TRH) to 200 amino acids (growth
hormone and prolactin)
more than100 amino acids – proteins
synthesized on the rough end of the ER
preprohormones – prohormones (ER) –
hormones (Golgi apparatus & secretory
vesicles) – exocytosis (Ca, cAMP)
2) Steroid Hormones
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usually synthesized from cholesterol
are not stored
lipid soluble
most of cholesterol comes from plasma, but
there is also de novo synthesis
consist of three cyclohexyl rings and one
cyclopentyl ring combined into a single
structure
3) Amine Hormones
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derived from tyrosine
most of the thyroid hormones combine with
plasma proteins
4x more epinephrine than norepinephrine
taken up into preformed vesicles and stored
until secreted (exocytosis)
in the plasma in free form or in conjugation
with other substances
Hormone Secretion
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some hormones (epinephrine) are secreted
within seconds after stimulation, and
develop action within seconds to minutes
thyroxine or growth hormone may require
months for full effect
concentrations of hormones are incredibly
small (from 10-12 to 10-6g/ml) – rates of
secretion are extremely small (μg-mg/day)
Control of Hormone Secretion
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in most instances – negative feedback
mechanisms
controlled variable is sometimes not the
secretory rate of the hormone itself but the
degree of activity of the target tissue
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regulation of gene transcription and
translation steps involved in the synthesis of
hormones and steps involved in processing
hormones or releasing stored hormones
positive feedback – LH, oxytocin
cyclical variations – seasonal changes,
various stages of development and aging,
the diurnal (daily) cycle, and sleep
Transport of Hormones in Blood
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water-soluble hormones (peptides and
catecholamines) – dissolved in the plasma
steroid and thyroid hormones – circulate in
the blood mainly bound to plasma proteins
(usually less than 10% free in solution),
biologically inactive (serve as reservoirs,
greatly slows their clearance from the
plasma)
Clearance of Hormones from Blood
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concentration of a hormone in the blood:
1)
rate of hormone secretion into the blood
2)
rate of removal of the hormone from the
blood (metabolic clearance rate –
number of milliliters of plasma cleared
of the hormone per minute)
one measures : the rate of disappearance of
hormone from the plasma & concentration
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2)
3)
4)
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metabolic destruction by the tissues
binding with the tissues
excretion by the liver into the bile
excretion by the kidneys into the urine
liver damage  excessively high
concentration of steroid hormones
half-life of angiotensin II < 1 minute,
thyroid hormones 1-6 days
Hormone Receptors and Their
Activation
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binding to specific receptors at the target
cell – first step of a hormone's action
initiation of a cascade of reactions in the
cell – amplification of the effect
hormonal receptors are large proteins, each
cell usually has some 2000 to 100,000
receptors
receptor is highly specific for a single
hormone
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2)
3)
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in or on the surface of the cell membrane
(protein, and catecholamine hormones)
in the cell cytoplasm (steroid hormones)
in the cell nucleus (thyroid hormones)
number of receptors usually does not
remain constant (increase or decrease)
Intracellular Signaling
formation a hormone-receptor complex
– alteration of function of receptor :
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ion channel-linked receptors
G protein-linked hormone receptors
enzyme-linked hormone receptors
intracellular hormone receptors and activation of genes
1) Ion Channel-Linked Receptors
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acetylcholine & norepinephrine
change in the structure of the receptor
opening or closing a channel for one or
more ions (Na, K, Ca)
few directly, most indirectly by coupling
with G protein-linked or enzyme-linked
receptors
2) G Protein-Linked Hormone Receptors
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heterotrimeric GTP-binding proteins
> 1000 known G protein-coupled receptors
all have 7 transmembrane segments that
loop in and out of the cell membrane
cytoplasmic tail is coupled to G protein
(include three parts – α, β, and γ subunits)
binding of hormone – conformational
change in receptor – activation of G protein
activated G proteins
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2)
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open or close cell membrane ion channels
change the activity of an enzyme in the cytoplasm
G proteins binds GDP (α subunit)
displacement of GDP by GTP causes the α
subunit to dissociate from the trimeric
complex and to associate with other
intracellular signaling proteins
inhibitory (Gi) & stimulatory (Gs) proteins
3) Enzyme-Linked Hormone Receptors
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some receptors, when activated, function
directly as enzymes or are closely
associated with enzymes that they activate
pass through the membrane only once
hormone-binding site on the outside of the
cell membrane
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catalytic or enzyme-binding site on the
inside
leptin receptor
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member of a large family of cytokine receptors that do
not themselves contain enzymatic activity but signal
through associated enzymes
one of the signaling pathways occurs through a
tyrosine kinase of the janus kinase (JAK) family,
JAK2
4) Intracellular Hormone Receptors and
Activation of Genes
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steroid hormones, thyroid hormones,
retinoid hormones, and vitamin D
receptors in the cytoplasm or nucleus
binding with a specific regulatory
(promoter) sequence of the DNA –
hormone response element
transcription of specific genes and
formation of mRNA
Second Messenger Mechanisms
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cAMP, cGMP
calcium ions and associated calmodulin
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4 binding sites for Ca, 3 or 4 changes its shape
activation/inactivation of protein kinases
phosphorylation of proteins (myosin light
chain kinase – smooth muscle contraction)
products of membrane phospholipid
breakdown
could be
Gi
amplification
of the effect –
cascade of
reactions
phosphatidylinositol
biphosphate
contraction,
secretion
Steroid Hormones Increase
Protein Synthesis
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these proteins then function as enzymes,
transport proteins, or structural proteins
aldosterone – for 45 minutes, protein which
promote sodium reabsorption and
potassium secretion
full action is delayed for at least 45
minutes-up to several hours or even day
Thyroid Hormones Increase Gene
Transcription in the Cell Nucleus
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thyroxine and triiodothyronine
bind directly with receptor proteins in the
nucleus (activated transcription factors
located within the chromosomal complex)
they control the function of the gene
promoters
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formation of many types of intracellular
proteins
thyroid hormones can continue to express
their control functions for days or even
weeks
Measurement of Hormone
Concentrations in the Blood
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extremely minute quantities (pg/mL)
radioimmunoassay
production of antibody that is highly specific
for the hormone to be measured is produced
small quantity of this antibody (smaller than
total possible) is mixed with:
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sample containing the hormone to be measured
appropriate amount of purified standard hormone
that has been tagged with a radioactive isotope
error of 10 to 15 percent
Measurement of Hormone
Concentrations in the Blood
ELISA (enzyme-linked immunosorbent
assay)
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it does not employ radioactive isotopes
much of the assay can be automated using 96-well
plates
cost-effective and accurate method for assessing
hormone levels