Transcript Hormones and Second Messengers

.
Biochemistry
Chen Yonggang
Dept. of Biochemistry
Zhejiang Univ. School of Medicine
E-mail: [email protected]
16-1
Integration of Metabolism
Functions of Hormones
16-2
Overview Of Metabolism
Adult animals reach a steady state where
anabolism and catabolism are
approximately equal.
Intercellular communication is
responsible for this steady state.
The nervous and endocrine systems are
responsible for coordinating
metabolism.
16-3
Overview of Metabolism-2
Neurons emit neurotransmitters that
evoke specific responses from nearby
cells.
Endocrine system releases hormones
into the bloodstream which act either
directly on a cell or via a second
messenger.
Overview of metabolism is on next slide.
16-4
16-5
Division of Labor
Small Intestine
Digestion of nutrients
Into molecules small enough to be
absorbed by enterocytes
To blood and lymph systems
Energy via glutamine
16-6
Division of Labor-2
Liver
Key role in carbohydrate, lipid, and AA
metabolism
Regulates composition of blood
Regulates nutrients availability
Adipose Tissue
Storage of energy in form of TAGs
16-7
Division of Labor-3
Brain
Directs most metabolic activity
Uses energy (usually glucose)
Kidney (energy via fatty acids and
glucose)
Filtration of blood plasma
Reabsorb electrolytes, sugars and
amino acids from filtrate
Regulate body pH
Regulate body’s water content
16-8
Feeding-Fasting Cycle
Mammals are able to consume food
intermittently because of elaborate
mechanisms for storing and mobilizing
energy-rich molecules derived from
food.
Postprandial-directly after a meal when
blood nutrient levels are elevated over
the fasting state.
Post absorptive- blood nutrient levels
are low, e. g. overnight.
16-9
The Feeding Phase
Food propelled along gastrointestinal
tract by muscular contraction (nervous
system).
Products are: sugars, fatty acids,
glycerol, and amino acids.
Sugars and amino acids absorbed and
transported by the portal blood to the
liver.
Lipids (as chylomicrons) to muscle and
adipose tissue. Chylomicron remnants
to liver.
16-10
The Feeding Phase-2
Glucose moves to the liver. High
concentration in blood triggers insulin
release in pancreas.
Insulin triggers: glucose uptake by muscle
and adipose tissue, fat synthesis in liver and
adipocytes, and gluconeogenesis (liver with
three C sources. Using excess amino acids
and lactate)
Allosteric effectors ensure that competing
pathways do not occur simultaneously.
16-11
The Fasting Phase
Nutrient flow from intestine decreases.
Blood glucose and insulin levels fall and
glucagon promotes glycogenolysis and
gluconeogenesis in the liver.
Low insulin levels promotes lipolysis
and release of AA from muscle.
Prolonged fasting (overnight) results in
FAs from adipose tissue providing
glucose for muscle.
16-12
The Fasting Phase-2
Starvation
FAs (adipocytes) and ketone bodies
(liver) are used for energy.
Large amounts of AAs from muscle are
used for gluconeogenesis.
After several weeks, the brain uses
ketone bodies for fuel.
16-13
Intercellular Communication
Endocrine hormones are chemicals
secreted by special cells that exert
some biochemical effect on a distant
target cell.
Growth hormone (pituitary), testosterone
(gonads), and insulin (pancreas) are
common examples.
Some hormones target specific cells and
some have effects on a variety of
different cell types.
16-14
Hormones
Thyroid-stimulating hormone (TSH)
stimulates follicular cells in the thyroid
gland to release T3 and T4.
T3 and T4 stimulate a variety of cellular
responses in numerous cell types.
Thyroid hormones stimulate
glycogenolysis in liver but glucose
absorption in the small intestine.
16-15
Hormone Examples
Source
Hormone
Function
Hypothalamu gonadotropin-RH stimulate
s
LH and FSH
Pituitary
growth hormone growth
oxytocin
uterine contr
Gonads
estrogens
female repr
androgens
male repr
Pancreas
insulin
glucose
uptake
16-16
Hormone Examples-2
Hormone molecules can be:
polypeptides: ACTH, FSH,
GnRH, oxytocin
steroids: estrogens, androgens,
glucocorticoids
AA derivatives: epinephrine,
thyroxine, norepinephrine
16-17
Cascade System-1
Many hormones synthesis and
release are regulated by a
“cascade mechanism” ultimately
controlled by the central nervous
system (CNS).
The hypothalamus directs the
anterior pituitary
(adenohypophysis) and posterior
pituitary (neurohypophysis).
16-18
Cascade System-2
hypothalamus
TRH
inhibit
CRH
GHRH
anterior pituitary
TSH
ACTH
thyroid
adrenal
cortex
T3, T4
GnRH
LH/FSH
testes
ovaries
corticoids
many tissues
GH
sex
hormones
reproductive
organs
bone
16-19
Cascade System-3
hypothalamus
posterior pituitary
oxytocin
smooth muscle
mammary glands
vassopressin
kidney tubules
arterioles
16-20
Growth Factors
A variety of hormonelike polypeptides
and proteins. Called growth factors or
cytokines, are thought to regulate the
growth, differentiation, and
proliferation of cells.
Epidermal growth factor (EGF)
A mitogen (a stimulator of cell division)
for many kinds of epithelial cells.
Platelet-derived growth factor (PDGF)
Stimulates mitosis in fibroblasts.
16-21
Growth Factors-2
Somatomedins (insulinlike growth
factors I and II, IGF-1 and IGF-2 in
humans)
Mediate actions of growth hormone
(GH).
Secreted in the liver (and other tissue
cells)
16-22
Growth Factors-3
Interleukin-2 (IL-2)
Also regulate the immune system.
Secreted by T cells after they have
been activated by binding to a
specific antigen-binding cell.
Numerous identical T cells are
produced.
16-23
Growth Factors-4
Interferons
Type I protect cells from viral infection
by stimulating phosphorylation and
inactivation of a protein factor
required for protein synthesis.
Type II (from T lymphocytes) inhibit
growth of cancerous cells.
Tumor necrosis factors (TNF) are toxic to
tumor cells.
16-24
Mechanisms of Hormone Action
Steroid receptors are usually within the
cell as the steroid molecules pass
through the cell membrane.
Other hormones bind to specific sites on
the cell membrane and release within
the cell second messengers which
actually cause the hormonal response.
This signal transduction also allows for
a tremendous amplification of the
hormone molecule’s impact on the cell.
16-25
Second Messengers
Common second
messengers are cyclic
NH2
AMP (cAMP), cGMP,
N
diacylglycerol (DAG),
N
inositol-1,4,5-triphosphate
N
N
2+
H
(IP3), and Ca .
CH2
O
We will examine cAMP
H
H
O
synthesis and action in
H
H
O
P
more detail.
O
OH
O
16-26
cAMP
cAMP is produced when hormone binds
to a membrane receptor. This binding
activates a G protein (binds guanine
nucleotide) as shown on the next slide.
The stimulated G protein replaces GDP
with GTP. This activates the a subunit
to bind to and activate adenylate
cyclase which then produces cAMP.
cAMP then activates a cAMP-dependent
protein kinase.
16-27
cAMP-2
hormone


a
inactive
G protein
GDP
adenylate
cyclase
hormone
GTP
GDP

active
G protein

a
GTP
adenylate
cyclase
(actived)
16-28
cAMP-3
Adenylate cyclase stays activated until
the GTP on the a subunit of the G
protein is hydrolyzed back to GDP.
Thus a single hormone molecule (eg.
glucagon) can stimulate synthesis of
many cAMP molecules which in turn
can turn on phosphorylation and
activate, for example, multiple
phosphorylase kinase molecules to
hydrolyze glycogen to G-1-P.
16-29
cAMP-4
Adenylate cyclase is deactivated when
the a subunit of the G protein uses its
built in hydrolysis capability to return
GTP to GDP.
Before this occurs, however, many
protein molecules have been activated.
This is the “cascade” process referred
to earlier.
16-30
cGMP
From GTP by guanylate cyclase
Two types of guanylate cyclase are
involved in signal transduction, one is
membrane bound and the other
cytoplasmic.
Membrane bound activated by:
Atrial natriuretic factor (ANF) peptide
Bacterial enterotoxin
16-31
cGMP-2
ANF is released by atrial heart cells
responding to increased blood volume.
Lowering blood pressure and diuresis
seem to be mediated by cGMP.
Binding of enterotoxin to intestinal cells
causes diarrhea via excessive
secretion of electrolytes and water into
the lumen of the small intestine.
Cytoplasmic guanylate cyclase may bind
NO to a heme group to activate the
enzyme.
16-32
Phosphatidyl Inositol and
2+
Ca
The phosphatidyl inositol cycle (slide 36)
mediates the action of hormones and
growth factors
Phosphatidyl inositol-4,5-bisphosphate
(PIP2) is cleaved by phospholipase C to
form second messengers DAG and IP3
(inositol-1,4,5-triphosphate)
DAG activates protein kinase which
activates or deactivates an enzyme.
16-33
Phosphatidyl Inositol and
2+
Ca -2
IP3 diffuses to the calcisome (SER,
smooth endoplasmic reticulum) where
it binds to a receptor, a calcium
channel.
Calcium flows in to the cytoplasm
regulating calcium-binding proteins.
Calmodulin mediates many calciumregulated reactions. It is a regulatory
subunit for some enzymes (e. g.
phosphorylase kinase important in
glycogen metabolism).
16-34
Fig 16.12
16-35
Steroid Hormone Mechanism
Signal transduction by hydrophobic
hormones (e. g. steroids) result in
changes in gene expression.
i. e. protein mix changes in the cell.
Transport into the cell is via binding to a
protein.
E. g. : transcortin
androgen-binding protein
sex hormone-binding protein
albumin
16-36
Steroid Hormone Mechanism-2
In the cell, hormones bind to
intracellular receptors. The complex
moves to the nucleus. (Slide 39)
In the nucleus, each complex binds to
specific DNA segments, called
hormone response elements (HRE), via
a zinc finger domain.
The receptor enhances or diminishes
transcription of a specific gene.
Each HRE may influence 50-100 genes.
16-37
16-38
The Insulin Receptor
The insulin receptor (Slide 41) is a transmembrane glycoprotein with two
subunits connected by disulfide
bridges.
Insulin binding activates receptor
tyrosine kinase activity and causes a
phosphorylation cascade that
modulates intracellular proteins.
Binding also induces transfer of some
proteins to the cell surface.
16-39
16-40
The End
Integration
of
Metabolism
16-41