Download Principles of Hormonal Integration

Principles of
Hormonal Integration
•
Endocrinological solutions to physiological
problems require integration of a large variety of
simultaneous events
•
Redundancy, is the excess of regulatory
capacity provided in the form of seemingly
duplicative or overlapping controls
•
Reinforcement, most hormones act at several
locales either within a single cell or in different
tissues or organs to produce separate but
mutually reinforcing responses
•
Push-pull mechanisms, many critical processes
are under dual control by agents that act
antagonistically either to stimulate or to inhibit
•
Modulation of responding systems, or the
relationship between amount of hormone
available and magnitude of the response, is
subjected to regulation by many factors,
including the action of other hormones
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Introduction
“story lines” and “circles
intersecting circles …”
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how many circles
do you see here ?
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Principles of Hormonal
Integration
(or how responses can
get complicated)
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Integration at the cellular level.
A cell may receive inputs from hormones A, B, and C simultaneously. Hormone B acting
through a G-protein coupled receptor activates adenylyl cyclase (AC) through the stimulatory subunit Gs. Hormone C binds to its G-protein coupled receptor, which inhibits
adenylyl cyclase through the inhibitory subunit Gi, and activates phospholipase C through
the Gq subunit, resulting in cleavage of phosphatidylinositol bis-phosphate (PIP2) and the
release of diacylglycerol (DAG) and inositol trisphosphate (IP3). Hormone A, acting through
a tyrosine kinase receptor, activates cyclic AMP phosphodiesterase (PDE), which degrades
cAMP.
The combined actions of the three hormones determines the concentration of cyclic AMP.
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
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Redundancy, is the excess of regulatory
capacity provided in the form of seemingly
duplicative or overlapping controls
Redundancy allows for physiological
adaptation when partial or even total failure of
an homeostatic mechanism occur and another
compensates for it
Strategies for therapeutic interventions,
designed to increase or decrease the rate of a
process, must take into account the redundant
inputs that regulate that process
Redundancy allows for adaptation of homeostatic
mechanisms to confront environmental changes
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
(e.g. at a tissue level)
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Redundant mechanisms to
stimulate hepatic glucose
production. Hormonal and neural
mechanisms are marshaled to
combat potentially life-threatening
low blood glucose concentrations.
Glucagon and epinephrin, two hormones from two
different tissues, produce the same end-result
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
(e.g. at a molecular level)
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Redundant mechanisms to
activate glycogen
phosphorylase by a single
hormone, epinephrine,
acting through both 1
and receptors.
Epinephrin increase glycogenolysis by two signal
transduction pathways to produce a same end-result
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Page 3
Principles of Hormonal
Integration
Idealized representation
of the effects of
epinephrine and growth
hormone on plasma
concentrations of free
fatty acids.
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
(e.g. at different time domains at the same site)
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Epi and GH increase plasma FFA at two different time
- domains for acute and susteined responses
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
(e.g. at different time domains at different sites)
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PTH and Vit D increase blood levels of calcium at
different target sites and at different time-domains
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Principles of Hormonal
Integration
Synergistic effects
of human growth
hormone (hGH)
and the synthetic
glucocorticoid
dexamethasone
(DEX) on lipolysis
as measured by
the increase in
glycerol release
from rat
adipocytes.
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
Both hGH and Dex
were somewhat
effective when
added individually,
but when added
together the
overall tissue
response was
greater than the
sum of the
responses
produced by each
hormone alone.
• Modulation of
Responding
Systems
(e.g. at the same time domain from different sites)
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GH and dexamethason increase lipolysis in a
synergistic way when administered simultaneously
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
Insulin has different effects in different ICF and
ECF places regarding fat storage
• Modulation of
Responding
Systems
Cortisol has different effects in different places
of different cells regarding gluconeogenesis.
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Reinforcement, most hormones act at several
locales either within a single cell or in different
tissues or organs to produce separate but
mutually reinforcing responses from the
perspective of the whole organism. For example:
Aldosterone has different effect in different
places of a single cell regarding Na reabsorption
Reinforcement involves multiple target homeostatic
activation to confront environmental changes
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Principles of Hormonal
Integration
• Redundancy
glycogen
glycogen phosphorilase
glycogen synthetase
G-1-P
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
G-6-Pase
glucose
hexokinase
glucose
G-6-P
F-6-P
PFK
F-1,6-diPase
F - 1,6 -diP
transaminases
insulin
glucagon
epinephrine
glucocorticoids
triose
amino acids
pyruvate
proteins
Krebs
cycle
acetyl CoA
fats
Insulin has different effects in different ICF and
ECF places regarding fat storage
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Insulin has different effects in different ICF and
ECF places regarding fat storage
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Increased uptake of glucose which serves as
substrate for fatty acid synthesis and for alphaglycerol phosphate to trap any FFA formed by
spontaneous lipolysis of triglyceride stores
Activate enzymes for fatty acid synthesis (e.g.
pyruvate dehydrogenase, pyruvate carboxylase,
acetyl-CoA carboxylase)
Inhibits breakdown of triglycerides already made
Induced synthesis of the ECF enzyme lipoprotein
lipase needed to take-up lipids from circulation
Insulin has different effects in different ICF and
ECF places regarding fat storage
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Principles of Hormonal
Integration
• Redundancy
glycogen
glycogen phosphorilase
glycogen synthetase
G-1-P
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
G-6-Pase
glucose
hexokinase
glucose
G-6-P
F-6-P
PFK
F-1,6-diPase
F - 1,6 -diP
transaminases
insulin
glucagon
epinephrine
glucocorticoids
triose
amino acids
pyruvate
proteins
Krebs
cycle
acetyl CoA
fats
Cortisol has different effects in different places
of different cells regarding gluconeogenesis
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E
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Cortisol has different effects in different places
of different cells regarding gluconeogenesis
S
E
Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Glucocorticoids promote protein breakdown
in muscle and lymphoid tissues and
consequently release of aminoacids into the
blood
In adipose tissue, glucocorticoids promote
triglyceride lipolysis and the release of
glycerol
In the liver, glucocorticoids induce the
formation of the enzymes necessary to
convert aminoacids, glycerol and other
substrates into glucose
Cortisol has different effects in different places
of different cells regarding gluconeogenesis
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Principles of Hormonal
Integration
• Redundancy
ALDO
its
mechanism
of action
include: serosal surface
• Reinforcement
1)
• Push-Pull
mechanisms
increase Na
permeability 2)
• Modulation of
Responding
Systems
increase
content of
Na/K
ATPases
3)
increases
ATP to Na / K
ATPases
luminal surface
Aldosterone has different effect in different
places of a single cell regarding Na reabsorption
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
S
Many critical processes are under dual control by
agents that act antagonistically either to stimulate or
to inhibit. Such dual control allows for a more precise
regulation than through negative feedback
Insulin and glucagon form a push-pull mechanism
controlling glucose output from liver which under
basal catabolic and anabolic conditions is controlled
by their negative feedbacks. In emergency situations
or during exercise Epi and Nepi release from adrenal
medulla and sympathetic nerve endings overide them
Another example of a push-pull mechanism is the
“switch” operated by glycogen phosphorylase and
glycogen synthetase, through their simultaneous
cAMP activation and inactivation by glucagon and
insulin, as well as by other hormones such as Epi
Push-pull mechanisms allow for a more precise regulation
than that produced by negative feedback
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
Push–pull
mechanism.
• Push-Pull
mechanisms
Epinephrine inhibits
insulin secretion
while promoting
glucagons
secretion. This
combination of
effects on the liver
stimulates glucose
production while
simultaneously
relieving an
inhibitory influence.
• Modulation of
Responding
Systems
(+) = increases
(-) = decreases
Insulin and glucagon form a push-pull
mechanism controlling glucose output from liver
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
S
Insulin and
form a
push-pull
AVP released
fromglucagon
the PP controls
water
permeability
mechanism
in controlling
the DCT andglucose
collectingoutput
ducts from liver
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
Push–pull
mechanism to
activate glycogen
phosphorylase while
simultaneously
inhibiting glycogen
synthase.
• Modulation of
Responding
Systems
S
Insulin and
form a
push-pull
AVP released
fromglucagon
the PP controls
water
permeability
mechanism
in controlling
the DCT andglucose
collectingoutput
ducts from liver
E
Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
S
Insulin and
form a
push-pull
AVP released
fromglucagon
the PP controls
water
permeability
mechanism
in controlling
the DCT andglucose
collectingoutput
ducts from liver
E
Page 11
Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Modulation of responding systems, or the relationship
between amount of hormone available and magnitude
of the response, is subjected to regulation by many
factors, including the action of other hormones
Two important determinants of the magnitude and the
duration of responses are the hormone concentration
present in the ECF sourrounding a target site and the
length of time that concentration is maintained. For
hormones having pulsatile release it means frequency
and amplitude of the hormone pulsatile release
Another important determinant of the magnitude and
the duration of the response are the sensitivity of target
tissues to hormonal stimulation and their capacity to
respond. Neither of them is constant and can be
modulated by other hormones
Modulation of responding systems relates to amount
of hormone available and magnitude of the response
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Modulation of responding systems relates to both the
magnitude and the duration of the hormonal response
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E
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
Modulation of responding systems relates to both the
magnitude and the duration of the hormonal response
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E
Principles of Hormonal
Integration
bound
hormone
( H R )
• Redundancy
binding
capacity
k1
• Reinforcement
H + R <------> H R
half
saturation
affinity = kd
k2
H* R
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
=
k1
= kd
k2
free hormone ( H )
Scatchard
plot
single binding
bound
/ free
HR /
H
slope = - 1 / kd
double
binding
capacity
bound hormo ne ( HR )
high affinity / low capacity
low affinity / high capacity
there are
four ways
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HR
A lower Km (response at half maximal velocity)
indicates the sensitivity of hormone-receptor binding
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Page 13
Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
The relationship between
concentration and response
at three different levels of
sensitivity. Arrows indicate
the concentration of
hormone that produces a
half-maximal response for
each level of sensitivity. Note
that the abscissa is plotted
on a logarithmic scale.
• Modulation of
Responding
Systems
1) modulation
of sensitivity
A lower Km (response at half maximal velocity)
indicates the sensitivity of hormone-receptor binding
Principles of Hormonal
Integration
Concentration
response
relationships
showing
different
capacities to
respond.
• Redundancy
• Reinforcement
Note that the
concentration
needed to
produce the
half maximal
response is
identical for
all three
response
capacities.
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
1) modulation
of sensitivity
Note that the
abscissa is
plotted on a
logarithmic
scale.
change in Vmax when Km is maintained indicates
changes in the capacity of the system to respond
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Principles of Hormonal
Integration
• Redundancy
• Reinforcement
The effects of up or down
regulation of receptor
number on sensitivity to
hormonal stimulation.
• Push-Pull
mechanisms
Note that the abscissa is
plotted on a logarithmic
scale.
• Modulation of
Responding
Systems
1) modulation
of sensitivity
main modulation paradigm is change of receptor #
rather than receptor affinity by covalent modification
Principles of Hormonal
Integration
• Redundancy
• Reinforcement
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
2) postreceptor
effects
20
number of
occupied
receptors 10
per cell
5
x 1000
0
biological
response
as % of
maximum
Specific
hormone
binding
0
% reduction
in the conc.
50 of receptors
75
88
100 Biological
response
50
0
-11
10
number of
receptors
occupied
for maximal
biological
response (100%)
-10
-9
-8
-7
10
10
10
10
hormone concentration (M)
Spare receptors, if fewer than 100% of receptors are
occupied to reach the maximal biological response
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Principles of Hormonal
Integration
• Redundancy
Spare
receptors.
Note that the
concentration
of hormone
needed to
produce a half
maximal
response is
considerably
lower than that
needed to
occupy half of
the receptors.
• Reinforcement
• Push-Pull
mechanisms
Note that the
abscissa is
plotted on a
logarithmic
scale.
• Modulation of
Responding
Systems
2) postreceptor
effects
Spare receptors, if fewer than 100% of receptors are
occupied to reach the maximal biological response
Principles of Hormonal
Integration
• Redundancy
E2
• Reinforcement
• Push-Pull
mechanisms
LH
• Modulation of
Responding
Systems
-Fb
3) abundance
of competent
target cells
+Fb
POA
phasic control of E2 on the preovulatory LH surge is
related to the increase abundance of granulosa cells
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Principles of Hormonal
Integration
• Redundancy
cAMP ----> PKA ----> channel / enzyme
R
AC
• Reinforcement
5
• Push-Pull
mechanisms
• Modulation of
Responding
Systems
4) permissive
actions
XX1
HRE
E1
Protein
synthesis
Na / K
pump
3
mRNA
Steroid S + R ----> SR
SR
DNA
addi tional
transc ription
factor
Spare receptors, if fewer than 100% of receptors are
occupied to reach the maximal biological response
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