Cell Surface Receptors
Protein and peptide hormones, catecholamines like epinephrine, and
eicosanoids such as prostaglandins find their receptors decorating
the plasma membrane of target cells.
Binding of hormone to receptor initiates a series of
events which leads to generation of so-called second messengers
within the cell (the hormone is the first messenger). The second
messengers then trigger a series of molecular interactions that
alter the physiologic state of the cell. Another term used to
describe this entire process is signal transduction.
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Structure of Cell Surface Receptors
Cell surface receptors are integral membrane
proteins and, as such, have regions that contribute to three basic
Extracellular domains: Some of the
residues exposed to the outside of the cell interact with and
bind the hormone - another term for these regions is the
Transmembrane domains: Hydrophobic
stretches of amino acids are "comfortable" in the lipid bilayer
and serve to anchor the receptor in the membrane.
Cytoplasmic or intracellular domains:
Tails or loops of the receptor that are within the cytoplasm
react to hormone binding by interacting in some way with other
molecules, leading to generation of second messengers.
Cytoplasmic residues of the receptor are thus the effector
region of the molecule.
Several distinctive variations in receptor structure
have been identified. As depicted below, some receptors are simple,
single-pass proteins; many growth factor receptors take this form.
Others, such as the receptor for insulin, have more than one
subunit. Another class, which includes the beta-adrenergic receptor,
is threaded through the membrane seven times.
Receptor molecules are neither isolated by themselves nor fixed in
one location of the plasma membrane. In some cases, other integral
membrane proteins interact with the receptor to modulate its
activity. Some types of receptors cluster together in the membrane
after binding hormone. Finally, as elaborated below, interaction of
the hormone-bound receptor with other membrane or cytoplasmic
proteins is the key to generation of second messengers and
transduction of the hormonal signal.
Surface receptors proteins sitting resident in
the cell's membrane (skin).
Each mode detailed on the left describes the method
and location of the site, some reacting outside of the cell, some
through the cell's skin and some with their tails hanging in the
cell's fluid to contact other parts of the cell via this fluid.
Second Messenger Systems
Consider what would happen if, late at night, you
noticed a building on fire. Hopefully, you would dial 911 or a
similar emergency number. You would inform the dispatcher of the
fire, and the dispatcher would, in turn, contact and "activate" a
number of firemen. The fire-fighters would then rapidly go to work
pouring water on the fire, setting up roadblocks and the like. They
would also probably activate other "players", such as police and
fire investigators that would come in later to try and determine the
cause of the fire. Importantly, once the fire is out (or the
building totally destroyed), the firemen go back to the station and
The community response to a fire is, at least in
some ways, analogous to a second messenger system involved in a
hormone's action. In the scenario described, you are the "first
messenger", the dispatcher is "receptor", the fire-fighters are
Currently, four second messenger systems are
recognized in cells, as summarized in the table below. Note that
not only do multiple hormones utilize the same second messenger
system, but a single hormone can utilize more than one system.
Understanding how cells integrate signals from several hormones into
a coherent biological response remains a challenge.
Examples of Hormones
Which Utilize This System
Epinephrine and norepinephrine, glucagon,
luteinising hormone, follicle stimulating hormone,
thyroid-stimulating hormone, calcitonin, parathyroid
hormone, antidiuretic hormone
Protein kinase activity
Insulin, growth hormone, prolactin, oxytocin,
erythropoietin, several growth factors
Calcium and/or phosphoinositides
Epinephrine and norepinephrine, angiotensin
II, antidiuretic hormone, gonadotropin-releasing hormone,
Atrial naturetic hormone, nitric oxide
In all cases, the seemingly small signal generated
by hormone binding its receptor is amplified within the cell into a
cascade of actions that changes the cell's physiologic state.
Presented below are two examples of second messenger systems
commonly used by hormones. The examples used are of glucagon and
insulin, both of which ultimately work through a molecular switch
involving protein phosphorylation. Be aware that in both cases, a
very complex system is being simplified considerably.
Second messenger systems are dispatchers,
triggering other reactions rather than doing the end job itself.
When a fore is reported, the dispatcher is the
receptor site which then dispatches the troops as required.
Because the troops do the actual work, they are secondary to the
call the dispatcher received.
This repeated messenger system has been identified
to go as deep as four levels.
Cyclic AMP Second Messenger Systems
Cyclic adenosine monophosphate (cAMP) is a
nucleotide generated from ATP through the action of the enzyme
adenylate cyclase. The intracellular concentration of cAMP is
increased or decreased by a variety of hormones and such
fluctuations affect a variety of cellular processes. One prominent
and important effect of elevated concentrations of cAMP is
activation of a cAMP-dependent protein kinase called protein kinase
Protein kinase A is nominally in an
catalytically-inactive state, but becomes active when it binds cAMP.
Upon activation, protein kinase A phosphorylates a number of other
proteins, many of which are themselves enzymes that are either
activated or suppressed by being phosphorylated. Such changes in
enzymatic activity within the cell clearly alter its state.
Now, let's put this information together to
understand the mechanism of action of a hormone like glucagon:
Glucagon binds its receptor in the plasma
membrane of target cells (e.g. hepatocytes).
Bound receptor interacts with and, through a set
of G proteins, turns on adenylate cyclase, which is also an
integral membrane protein.
Activated adenylate cyclase begins to convert
ATP to cyclic AMP, resulting in an elevated intracellular
concentration of cAMP.
High levels of cAMP in the cytosol make it
probable that protein kinase A will be bound by cAMP and
therefore catalytically active.
Active protein kinase A "runs around the cell"
adding phosphates to other enzymes, thereby changing their
conformation and modulating their catalytic activity - - -
abracadabra, the cell has been changed!
Levels of cAMP decrease due to destruction by
cAMP-phosphodiesterase and the inactivation of adenylate cyclase.
In the above example, the hormone's action was to
modify the activity of pre-existing components in the cell.
Elevations in cAMP also have important effects on transcription of
Some cells act hormonally upon themselves as
well as responding to outside influences. The way the body
makes ATP, the final form of fuel we burn at a cellular level is a
good example. If we were to wait until the brain decided we
needed more fuel, each cell that is active will be running out.
Burning of a fuel can itself produce hormonal
stimulation of the cell doing the burning of that fuel.
Tyrosine Kinase Second Messenger Systems
The receptors for several protein hormones are
themselves protein kinases which are switched on by binding of
hormone. The kinase activity associated with such receptors results
in phosphorylation of tyrosine residues on other proteins. Insulin
is an example of a hormone whose receptor is a tyrosine kinase.
The hormone binds to domains exposed on the cell's
surface, resulting in a conformational change that activates kinase
domains located in the cytoplasmic regions of the receptor. In many
cases, the receptor phosphorylates itself as part of the kinase
activation process. The activated receptor phosphorylates a variety
of intracellular targets, many of which are enzymes that become
activated or are inactivated upon phosphorylation.
As was seen with cAMP second messenger systems,
activation of receptor tyrosine kinases leads to rapid modulation in
a number of target proteins within the cell. Interestingly, some of
the targets of receptor kinases are protein phosphatases which, upon
activation by receptor tyrosine kinase, become competent to remove
phosphates from other proteins and alter their activity. Again, a
seemingly small change due to hormone binding is amplified into a
multitude of effects within the cell.
In some cases, binding of hormone to a surface
receptor induces a tyrosine kinase cascade even through the receptor
is not itself a tyrosine kinase. The growth hormone receptor is one
example of such a system - the interaction of growth hormone with
its receptor leads to activation of cytoplasmic tyrosine kinases,
with results conceptually similar to that seen with receptor kinases.
The lay person does not need to understand
this section unless motivated to study the intricacies of the left
Fate of the Hormone-Receptor Complex
Normal cell function depends upon second messenger
cascades being transient events. Indeed, a number of cancers are
associated with receptors that continually stimulate second
messenger systems. One important part of negative regulation on
hormone action is that cell surface receptors are internalized. In
many cases, internalization is stimulated by hormone binding.
Internalization occurs by endocytosis through
structures called coated pits. The resulting endosomes (sometimes
called "receptosomes") may fuse with lysosomes, leading to
destruction of the receptor and hormone. In other cases, it appears
that the hormone dissociates and the receptor is recycled by fusion
of the endosome back into the plasma membrane.
The technical information on these pages is the work of
Professor Bowen et al, Colorado State University and are reproduced
without endorsement of any kind. The "lay" interpretations are
the work of this site and do not necessarily reflect Professor