1-IFM AF EndoPrinciples Signaling 2016 PDF

Medical Physiology, Page 1 of 12
Endocrine Principles
and Signaling Mechanisms

MEDICAL PHYSIOLOGY: Endocrine Physiology
Endocrine Principles and Signaling Mechanisms

Lecturer: Alessandro Fatatis, M.D, Ph.D.
E-‐‑mail: afatatis@drexelmed.edu
Self Study

LEARNING OBJECTIVES
Upon studying the material in these notes you should be able to:
1 Define hormone, target cell, and receptor.
2 Understand the terms endocrine, neurocrine, paracrine, and autocrine based on the site of
hormone release and the pathway to the target tissue.
3 Recognize the difference between hydrophilic and hydrophobic hormones, first and
second messengers (signal transduction), cell surface, and intracellular receptors.
4 Compare and contrast hormone actions that are exerted through changes in gene
expression with those exerted through changes in protein phosphorylation.
5 Recognize the effects of secretion, excretion, and degradation on the concentration of a
hormone in blood plasma and understand the concept of metabolic clearance rate.
6 Understand the effects of plasma binding protein on the access of hormones to their site of
action and degradation and explain the basis of hormone measurements.
7 Understand the relationship between concentration of a hormone and the biological
response. Apply this relationship to changes in cell receptor density (i.e., up-‐‑regulation
and down-‐‑regulation) or receptor sensitivity.

Definition of a Hormone:

A hormone is a chemical substance secreted by
specialized cell types and carried by the blood
stream to act on distant target cells.

A key role for hormones is to implement
homeostasis. Homeostasis is defined as the
maintenance of steady states in the body by
coordinated physiologic mechanisms.
Exchanges of matter and energy between the
external environment and the internal milieu
of our body need to be regulated in a finely
tuned fashion. Particularly important events
that are regulated by hormones include:
a) oxygen and carbon dioxide tensions; b)
concentrations of glucose and other (Medical Physiology 4 ed., Rhoades and Bell, p. 2)
th
metabolites; c) osmotic pressure; d)

concentrations of different ions; e) temperature.

The same paradigm applies when considering the intracellular environment and the interactions with
the extracellular fluid and its components. Hormones are equally responsible to regulate the
exchanges occurring between these two compartments.

In addition to central regulators of homeostasis, we now recognize that hormones exert fundamental
roles in a variety of cellular activities and body functions that may not be directly correlated with it.
Some of them are as follows:

• Cellular proliferation

• Cellular differentiation

• Growth and maturation

• Reproduction

• Senescence

• Behavior

Finally, it is also important to
remember that hormones are
produced and secreted not only by
anatomically recognized endocrine
glands, but also by many cells with
endocrine functions.

Modes of communication and signaling and the role of hormones

Local communication:
Autocrine
The cell releases a chemical messenger that remains in the surrounding extracellular fluid and
binds to a receptor on the surface of the same cell.
A typical example of this mode of communication is offered by Eicosanoids (Prostaglandins).
These hormones regulate local processes such as uterine smooth muscle contraction during
pregnancy.

Paracrine
The chemical messenger is released from a cell and act on a nearby cell after diffusing for a
short distance. Thus, hormones acting in this fashion can only affect the immediate
environment. Extracellular enzymes rapidly destroy paracrine hormones to avoid their
diffusion to distant sites.
A typical hormone with
paracrine mode of action is
nitric oxide, which among
other effects regulates the
tone of smooth muscle
cells.

Distant communication:
Neuroendocrine
This mode of
communication pertains to
nervous cells. Neurons
normally communicate by
releasing neurotransmitter
at a synapse. Neuro-‐‑
hormones are produced by
neurons and released
through the axon but in the
blood stream, in which
they circulate to reach
distant target cells

Endocrine
Endocrine glands and cells
secrete hormones directly
in the blood stream, often
trough specialized portion
of the plasma membrane
that are located on one side
of the cell body (cell
polarization).

Hormone classification
Hormones can be classified (Medical Physiology 4 ed., Rhoades and Bell, p. 6)
th
according to different criteria.

These classifications, hydrophilic and hydrophobic incorporate their physico-‐‑chemical characteristics,
which inevitably dictate their biosynthetic processes, secretion, transport in the plasma and clearance
from the body, mechanisms of action, etc.

Hydrophilic hormones: These molecules dissolve well in water since they are often polar and
charged. Consequently, they dissolve easily in the blood and can be stored in secretory
vesicles because the hydrophobic phospholipid bilayer will contain them until secretion
occurs.

Hydrophobic hormones: These hormones do not dissolve well in water-‐‑rich environments, as
they are often non-‐‑polar and uncharged. Therefore, carrier proteins are needed to allow their
transport in the plasma. Finally, hydrophobic hormones cannot be contained in secretory
vesicles but are almost invariably secreted from the producing cells immediately after their
synthesis.

HYDROPHILIC HORMONES AND THEIR SIGNALING

Amine hormones: Catecholamine hormones derive from the amino acid tyrosine.
Thyroid hormones also derive from tyrosine, but have a hydrophobic
structure. Dopamine and norepinephrine also act as neurotransmitters
in the Central Nervous System (CNS), whereas epinephrine is
exclusively produced outside of the CNS.

Peptide hormones: Peptide hormones are produced by the pituitary gland as releasing
factors (RF) acting on peripheral endocrine glands such as thyroid,
gonads and adrenal gland. Insulin is also a peptide hormone produced
by the endocrine pancreas.

Processing of peptide hormones.
Insulin is a typical example of peptide hormones that are processed before being secreted in the blood
stream. From an initial precursor located in the endoplasmic reticulum (ER) called Pre-‐‑Pro Insulin, the
C Peptide induces a particular tridimensional conformation that allows the cross-‐‑binding of the Pro
Insulin and is then transferred to the Golgi apparatus, where the C peptide is cleaved off and
included in secretory vesicles along with Insulin, at this point formed by the A and B chains bound
together. The C peptide exerts no physiological functions, but it can be measured in the plasma and
provide indication of the amount of insulin secreted by the pancreas. Additional details about these
issues will be discussed in the lecture on the Endocrine Pancreas.

Hydrophilic hormones are unable to cross the plasma membrane. Therefore, in order to transmit the
signal they carry inside the cells, two conditions are necessary:

a) The receptor for this class of hormones must reside on the cell surface

b) The transmission of the signal from the plasma membrane to intracellular targets is
assigned to “second messengers”. This definition derives from considering the hormone the
“first messenger”.

Several types of second messengers exist in eukaryotic cells. Their production, upon stimulation of a
plasma membrane receptor by hormones, involves transducers and intracellular effectors. These two
components of the intracellular signaling machinery act in sequence – with upstream and
downstream molecules – and generate second messengers. The concerted actions of transducers,
effectors and second
messengers generate
signaling pathways that are
responsible for a cadre of
cellular responses (Figure 4;
page 4).

Transducers: These
molecular mediators are
tightly associated with the
plasma membrane receptors.
See below for the two main
classes of hormone receptors.

Effectors: These are enzymes
responsible to receive the
input form transducers and
produce the second
messengers. Some examples
are Adenylyl Cyclase and
Phospholipase C (PLC).

Second messengers: some of
the most studied and well
(Medical Physiology 4 ed., Rhoades and
th
characterized are: Bell, p. 9)

• Cyclic adenosine
monophosphate
(cAMP) (Medical Physiology 4 ed., Rhoades and Bell, p. 11)
th
• Cyclic guanosine
monophosphate
(cGMP)
• Inositol-1,4,5-
triphosphate (IP3)
• Diacylglycerol (DAG)
• Calcium (Ca++)
• Arachidonic acid

Membrane receptors for
hydrophilic hormones.
Two main classes of
receptors, G protein-‐‑coupled receptors (GPCRs) and Tyrosine Kinase Receptors (TKRs), are located on
the surface of cells in order to bind hydrophilic hormones:

1) G protein-‐‑coupled receptors (GPCRs).
This class of receptors includes more than 1,000 molecular entities and use trimeric G proteins as
transducers. These receptors share a very similar molecular structure shared by all members, with
seven transmembrane-‐‑spanning regions, a ligand-‐‑binding domain located on the extracellular amino
terminal and a binding site for the G proteins located on the intracellular carboxy-‐‑terminal.
The binding of the hormone induces a conformational change in the receptor that eventually results in
the binding of its intracellular portion with a G protein. Upon binding with the activated receptor, the
G protein exchanges a molecule of GDP (guanosine-‐‑diphosphate) with GTP and dissociates in alpha
and beta-‐‑gamma subunits,
which will activate different
effectors. The hydrolysis of
GTP into GDP by the alpha
subunit will then induce re-‐‑
association of the three sub-‐‑
units and displacement of the
G protein from the receptor.

Several types of G proteins
exist and the same receptor
can activate more than one
type. Thus, the same
hormone may activate the
same receptor in different !
cells or tissues and generate distinct – and sometimes A. Fatatis and M. Russell, 2008.
opposite – cellular responses. This is due to the fact that the
same effector enzyme can be activated by one type of G
protein and inhibited by another type.

2) Tyrosine Kinase Receptors (TKRs).
This family of membrane receptors is less homogeneous than the GPCRs. However, a prototypical
TKR will be organized with an extracellular domain to bind the hormone, a short trans-‐‑membrane
portion and a cytoplasmic portion that contains a kinase domain. TKRs exist as monomers and upon
binding they commonly dimerize. This process brings the cytoplasmic tails of each receptor in close
proximity and induces a conformational change and activation of the kinase domain. The resulting
trans-‐‑phosphorylation of specific cytoplasmic portions of each receptor generates docking-‐‑sites for
effector molecules that bind through a specific sequence called SH2-‐‑domain.

HYDROPHOBIC HORMONES AND THEIR SIGNALING
Each class of hydrophobic hormones derive from a common precursor:
Steroids derive from
cholesterol, thyroid hormones
from the amino acid tyrosine
and eicosanoids from
arachidonic acid.
Minimal changes to the
common chemical structure of
steroids will produce
hormones with significantly
different physiological actions.
It is also worth to remember
that thyroid hormones are
stored within the producing
cells despite their hydrophobic
nature. Another exception to
the rule is represented by
Eicosanoids, which despite
being hydrophobic, bind and
activate receptors expressed
on the surface of the target
cells.
th
Bell, p. 16)
Intracellular receptors for hydrophobic hormones
Hydrophobic hormones are lipid-‐‑soluble and therefore can easily cross the plasma membrane to
interact with their receptors. The intracellular receptors can be located either in the cytosol (Type I) or
in the nucleus (Type II). Steroid hormones (glucocorticoids and mineralocorticoids) use Type I
receptors that they bind once inside the cell.
The hormone-‐‑receptor complex moves into the nucleus and binds to specific DNA sequences
responsible for regulating gene expression, called promoters. The sequence in the promoter that binds
the hormone-‐‑receptor complex is called the Hormone Response Element (HRE). The interaction with
the promoter can inhibit gene expression but in the majority of circumstances will promote the
expression of specific genes through the synthesis of messenger RNA (mRNA), which codes for
specific proteins. The mRNA leaves the nucleus, passes into the cytoplasm of the cell, and binds to
ribosomes, where it directs the synthesis of specific proteins. The proteins synthesized on the
ribosomes produce the response of the cell to the hormone.

In contrast to what is described above, vitamins A and D, retinoids and thyroid hormones all use
Type II intracellular receptors, which are already bound to DNA. In this case, the hormones need to
travel through the cytoplasm, cross the nuclear envelope and then bind their receptors. Type II
receptors are inactive when unoccupied by the hormone and act as repressors of gene expression
when in the inactivated state.

It is important to understand the differences in receptor location, the need for second messengers, and
finally the different time frame necessary for the actions of hydrophilic and hydrophobic hormones to
take place.

Storage and secretion of
hormones
As mentioned above
hydrophobic hormones are not
normally stored in the
producing cells but they simply
diffuse out of the cell and into
the plasma.
In contrast, hydrophilic
hormones can be stored in
cytoplasmic vesicles and
therefore accumulates during
times in which their secretion is not required or does not need to be very intense.
Secretion will occur when – upon activation of cellular receptors – the concerted action of G proteins
and the enzyme phospholipase C (PLC) will produce the second messenger inositol trisphosphate
(IP3). The binding of IP3 to receptors located on specific compartments of the endoplasmic reticulum
will release stored calcium ions (Ca2+) into the cytosol. This event will then facilitate the fusion of
hormone-‐‑containing vesicles with the plasma membrane. The simultaneous production of additional
second messengers – such as adenosine monophosphate
th
(AMP) and guanine monophosphate (GMP) – is also Bell, p. 596)
capable of modulating the

process of hormone
secretion.

Hormone transport
The majority of
hydrophilic hormones
(Protein hormones and
Catecholamines)
normally circulate in the
plasma in their free form.
In contrast, hydrophobic
hormones (steroid and
thyroid hormones)
circulate bound to
specific globulins. These
complexes increase the
solubility of hydrophobic hormones in the plasma’s aqueous environment and increase their
distribution in different tissues.

The half-‐‑life of a hormone is the time needed for one-‐‑half of a hormone to disappear from the plasma.
The free form of a hormone (not bound to a carrier protein) is also active and only capable of
activating cellular receptors. In addition, free hormones are available to be degraded and successively
cleared from the plasma and excreted from the body. Therefore, the half-‐‑life of a hormone is
predominantly correlated to the percentage of it that is bound to carrier proteins at any given time.
Hormones that circulate mostly bound to carrier proteins will have a longer half-‐‑life as compared to
hormones that circulate in a free form.

Hormone disposal
The removal of a hormone from the body is the results of:

• Uptake and degradation
operated by target cells. mg/min#removed#
• Metabolic degradation MCR#=## ml#plasma/min#
(predominantly by the liver). [mg/ml]#in#plasma#
• Urinary or biliary excretion
To$be$measured$in$$ Added$during$the$assay$
biological$ﬂuids$
The kinetic and efficiency of the
elimination of a hormone from the
plasma can be measured and
monitored with the Metabolic
Clearance Rate (MCR):

Measurement of hormone
concentrations
The most common and useful methods
for measuring hormones in biological
fluids are immunoassay-‐‑based
approaches such as the
Radioimmunoassay (RIA) and
enzyme-‐‑linked immunosorbent assay
(ELISA).

In RIA, monoclonal antibodies bind to
a radioactive form of the same
hormone that needs to be measured in
biological fluids. The hormone in the
unknown sample will compete with the
radioactive hormone in binding to the
antibody. The higher the concentration
(Medical Physiology 4 ed., Rhoades and Bell, p. 599) Modified by A. Fatatis
th
of the hormone in the unknown sample

the lower the radioactivity in the antibody complex. This is indicated by a RIA standard curve, in
which the (non-‐‑radioactive) hormone to be measured progressively reduces the concentrations of the
radioactive hormone bound to the antibody, depending on its concentration in the unknown sample.

ELISA is more frequently used both in the
hospital setting and over the counter
diagnostic tests.

An antibody is bound to a substrate and
captures the hormone from the biological
sample. A second or third antibody –
conjugated with an enzyme -‐‑ will detect the
captured hormone and catalyze a reaction in
which a substrate is converted into a colored
or fluorescent product. The intensity of the
colorimetric or fluorescent reaction indicates
the concentration of the hormone in the
sample.
In a minority of cases, biological assays may

be necessary to obtain correct physiological
or diagnostic information. For example,
when the activity of a hormone changes
depending not on its concentration but the
(Medical Physiology 4 ed., Rhoades and Bell, p.
th
level of glycosylation. In this case, an 600)

immunoassay will fail to discriminate
between the active and inactive forms of a hormone.

Additional regulation of hormonal secretion
It is also important to recognize that hormone secretion can be regulate by:

A. Pulsatile vs. Steady-‐‑state release

B. Other oscillating factors
i. Development (growth vs. maintenance)
ii. Menstrual cycle
iii. Seasonal
iv. Circadian (or daily variance

C. Feedback control
i. Positive feedback These concepts will be addressed
ii. Negative feedback in the next lecture

Regulation of hormone receptor functioning

Receptor down-‐‑regulation
The number of cellular receptors for a given hormone expressed on the cell surface can frequently
decrease due to physiological and regulatory events as well as pathological conditions.
A reduction in number may occur, for example, as a compensating response to exaggerated increases
in the plasma levels of a hormone. The binding of the hormone to its receptors induces the
endocytosis of the receptor and/or its inactivation. Pathological conditions may be associated to
autoantibodies, which target specific hormone receptors, thereby inducing a down-‐‑regulation of the
effects observed on target cells. Finally, a functional down-‐‑regulation may be associated with a
reduced affinity of a hormone for its receptor, even in the presence of a normal number of receptors
on the cell surface. A typical example is represented by insulin in Diabetes Type-‐‑II.

Receptor up-‐‑regulation
This condition can be the result of a compensatory measure in normal cells for a reduction in the
levels of a hormone in the interstitial fluid. In cancer cells, over-‐‑expression of hormone receptors,
often acting as oncogenes, can also be observed.
Receptor down-‐‑regulation and up-‐‑regulation determine dose-‐‑response relations and directly dictate
the changes in responsiveness and sensitivity to a hormone.

Dose-‐‑response relationship
This is the relationship between the dose of a hormone and the resulting biological response
observed in the target cells and expected changes in body functions.

Responsiveness to a hormone
Panel A (see page 12) indicates the maximum functional response that can be obtained by
progressively increasing the endogenous concentrations (or therapeutically administered doses) of a
hormone. This phenomenon depends on the number of functional receptors expressed as well as the
maximum possible number of transducers, effectors and second messengers that can be recruited
from the receptors in a given time. In case of a reduction in responsiveness affecting a given hormone
receptor, the increase in hormone concentration will not produce any relevant increase in the
biological response, since the excess of ligand cannot be matched by a comparable number of
receptors or transducers.

Sensitivity to a hormone
It refers to the affinity between a hormone and its receptors. Sensitivity is measured as the
concentration of a hormone capable of inducing 50% of the maximal response (see Panel B on next
page).


(Medical Physiology 4 ed., Rhoades and Bell, p. 602) Modified by A. Fatatis

th

A reduction in sensitivity is conventionally represented as a “shift to the right” of the dose-‐‑response
curve. This is the expression of the need for higher concentrations of a hormone in order to induce the
50% of maximal response. A reduction in sensitivity can be compensated for – at least temporarily –
with an increase in hormone concentration.

Suggested Resources:

1. Rhoades and Bell. Medical Physiology, Fourth Edition, 2012, Chapters 1 and 30.
2. Berne, Levy, Koeppen, Stanton. Physiology, Fifth Edition, 2004, Chapter 39.
3. Costanzo, Third Edition, 2006, Chapter 9, pages 377-‐‑387.

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Medical Physiology, Page 1 of 12

metabolites; c) osmotic pressure; d)

according to different criteria.

characterized are: Bell, p. 9)

(AMP) and guanine monophosphate (GMP) – is also Bell, p. 596)

capable of modulating the

of the hormone in the unknown sample

In a minority of cases, biological assays may

level of glycosylation. In this case, an 600)

(Medical Physiology 4 ed., Rhoades and Bell, p. 602) Modified by A. Fatatis

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