Chapter 5 – Chemical Messengers
Human Physiology 135-152
I.
Receptors  Table 5-1, page 137 (Glossary of terms)
Receptor: A specific protein in either the plasma membrane or
interior of a target cell with which a chemical messenger
combines.
Specificity: The ability of a receptor to bind only one type or a
limited number of structurally related types of chemical
messengers.
Saturation: The degree to which receptors are occupied by a
messenger. If all are occupied, the receptors are fully saturated;
if half are occupied, the saturation is 50 percent, and so on.
Affinity: The strength with which a chemical messenger binds to
its receptor.
Competition: The ability of different molecules very similar in
structure to combine with the same receptor.
Antagonist: A molecule that competes for a receptor with a
chemical messenger normally present in the body. The
antagonist binds to the receptor but does not trigger the cell's
response.
Agonist: A chemical messenger that binds to a receptor and
triggers the cell's response; often refers to a drug that mimics a
normal messenger's action.
Down regulation: A decrease in the total number of target-cell
receptors for a given messenger in response to chronic high
extracellular concentration of the messenger.
Up-regulation: An increase in the total number of target-cell
receptors for a given messenger in response to a chronic low
extracellular concentration of the messenger.
Supersensitivity: The increased responsiveness of a target cell
to a given messenger, resulting from up-regulation.
A.
First step in action of a chemical messenger is to bind to specific
protein molecules on the "target cell" - the term "target cell" is a
misnomer
1.
DO NOT CONFUSE THE USE OF THE WORD RECEPTOR
AS USED HERE WITH SENSORY RECEPTOR OR
DETECTOR!
2.
Chemical messenger is called the ligand and receptor is
binding site
a)
Plasma-membrane receptors are transmembrane
proteins  they span the entire membrane thickness
b)
Receptors may be inside the cell, the cytosol
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Chapter 5 – Chemical Messengers
Human Physiology 135-152
3.
B.
C.
It is at the plasma membrane receptor-messenger binding
that specificity is determined - Figure 5-1, page 137
a)
The cell "chooses" the messenger, the messenger
doesn't "find" or "target" the cell"
b)
The nature of the receptors that are associated with
the plasma membrane determine what messengers
it will respond to and thus determine specificity 
Figure 5-2, page 138
c)
The nuclear DNA dictates and governs which
receptors and how many will be "sent" to the
membrane (see Chapter 2 for review)
d)
Some receptors are also enzymes, i.e., protein
kinase C more later in chapter
e)
This as one of the most active areas of research
being conducted now - as predicted, the membrane
receptors are all important in determining many
biological functions
Characteristics
1.
Specificity - see above
2.
Can have several different receptors for same messenger,
resulting in different responses
3.
Receptors can have different affinities for messengers
4.
Messenger-receptor interactions include
a)
Saturability - finite number of receptors per cell
b)
Competition - antagonists bind to receptor instead of
"normal" messenger
c)
Agonists - mimic "normal" messenger
Regulation of receptors
1.
The number of receptors on a membrane can be altered by
the cell and/or the affinity can be altered
a)
Fewer receptors  down-regulation: decrease in
number of effector-cell receptors for a given
messenger in response to a chronic high
concentration of that messenger
More receptors  up-regulation: increase in
number of effector-cell receptors for given
messenger in response to chronic low extracellular
concentrations of that messenger
2.
Mechanism: some hormones induce endocytosis of the
"target cell" and thus the receptors are degraded and downregulation occurs  myasthenia gravis is caused by
destruction of skeletal muscle receptor for acetylcholine
Signal Transduction Pathways, Text page 139
b)
II.
A.
Receptor activation
1.
Change in membrane permeability, transport or electrical
state
2.
The rate at which a particular substance is synthesized or
secreted by the cell
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Chapter 5 – Chemical Messengers
Human Physiology 135-152
3.
4.
B.
C.
D.
The cell's rate of proliferation and differentiation
The cell's contractile activity (e.g., skeletal muscle, saliva
glands, gall bladder)
5.
There will be more examples later such as blocking
polyspermy in fertilization
Classification of plasma-membrane receptors based on the signal
transduction mechanisms - Table 5-2, page 140
Intracellular Receptors (for lipid-soluble messengers) Function in
the nucleus as transcription factors to alter the rate of transcription
of particular genes
1.
Lipid-soluble messengers bind to receptors inside the target
cell
a)
More description in Chapter 11
b)
Mostly steroid hormones - Figure 5-3, page 140
2.
The activated receptor acts in the nucleus as a transcription
factor to alter the rate of transcription of specific genes
3.
Results in a change in the concentration of the protein in the
cell or its rate of secretion from the cell
Plasma-Membrane Receptors (for lipid-insoluble messengers)
1.
Terminology
a)
First messengers
b)
Second messengers
Protein kinase  any enzyme that transfers a
phosphate from ATP to the another protein (known
as phosphorylation)
(1)
Alters the recipient protein, either activating
it or changing its conformation
(2)
The activated protein then is involved a
cellular pathway leading to a response
The receptor may contain an ion channel, which opens,
resulting in an electric signal in the membrane and, when
calcium channels are involved. an increase in the cytosolic
calcium concentration, Figure 5-4 (A), page 141
Tyrosine-kinase receptors: the receptor may itself act as an
enzyme. The most common enzyme activity is that of a
protein kinase, specifically a tyrosine kinase, Figure 5-4
(B), page 141
a)
An extracellular ligand-binding domain and a
cytosolic domain possessing tyrosine kinase enzyme
activity characterize the structure of a tyrosinekinase receptor. Examples of tyrosine-kinase
receptors are the receptors for numerous growth
factors, such as PDGFs, the family of factors that
serve as external modulators of the cell-cycle control
system.
b)
Propagation of the signal involves several steps as
follows:
(1)
Ligand binding causes aggregation of two
receptor units, forming receptor dimers.
c)
2.
3.
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Human Physiology 135-152
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4.
5.
Aggregation activates the endogenous
tyrosine kinase activity on the cytoplasmic
domains.
(3)
The endogenous tyrosine kinase catalyzes
the transfer of phosphate groups from ATP
to the amino acid tyrosine contained in a
particular protein. In this case, the tyrosines
that are phosphorylated are in the
cytoplasmic domain of the tyrosine-kinase
receptor itself (thus, this step is an
autophosphorylation).
(4)
The phosphorylated domain of the receptor
interacts with other cellular proteins,
resulting in the activation of a second, or
relay, protein. The relay proteins may or
may not be phosphorylated by the tyrosine
kinase of the receptor. Many different relay
proteins may be activated, each leading to
the initiation of many, possibly different,
transduction systems.
(5)
One of the activated relay proteins may be
protein phosphatase, an enzyme that
hydrolyzes phosphate groups off of proteins.
The dephosphorylation of the tyrosines on
the tyrosine kinase domain of the receptor
results in inactivating the receptor and the
termination of the signal process.
Receptors that activates JAK kinase in the cytoplasm, Figure
5-4 (C), page 141
a)
The enzymatic activity resides not in the receptor but
in a family of separate cytoplasmic kinases, termed
JAK kinases, which are bound to the receptor (JAK
= Just Another Kinase)
b)
The receptor and its associated JAK kinase function
as a unit; the binding of a first messenger to the
receptor causes a conformational change in the
receptor that leads to activation of the JAK kinase
c)
Different receptors associate with different members
of the JAK kinase family, and the different JAK
kinases phosphorylate different target proteins,
many of which act as transcription factors
d)
The result of these pathways is the synthesis of new
proteins, which mediate the cell's response to the
first messenger
The receptor may interact with an associated
plasma-membrane G protein, which in turn interacts with
plasma-membrane effector proteins (ion channels or
enzymes), Figure 5-4 (D), page 41
a)
Act as a couple to a variety of plasma-membrane
effector proteins - ion channels and enzymes –
which in turn induce a variety of cellular events
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Chapter 5 – Chemical Messengers
Human Physiology 135-152
b)
E.
Most important are adenylyl cyclase and
phospholipase C
c)
The receptor may activate, via a Gs protein, or
inhibit, via a Gi protein, the membrane effector
enzyme adenylyl cyclase, which catalyzes the
conversion of cytosolic ATP to cyclic AMP. Cyclic
AMP acts as a second messenger to activate
intracellular cAMP-dependent protein kinase, which
phosphorylates proteins that mediate the cell's
ultimate responses to the first messenger (next
topic)
Adenylyl cyclase and cyclic AMP - Figure 5-5, page 143
1.
G Protein activation - Nobel Prize in 1994 to Alfred G.
Gilman and Martin Rodbell for their discovery of G-proteins
and the role of these proteins in signal transduction in cells.
a)
In the inactive state G proteins are bound to
guanosine diphosphate (GDP). The activated
receptor causes the G protein to give up the GDP
and bind instead guanosine triphosphate (GTP)
(1)
This binding of GTP that activates the G
protein, allowing it to interact with an effector
protein.
(2)
Activation is brief because activated G
protein also functions as an enzyme that
splits off a phosphate from the GTP, thereby
returning to its GDP-bound inactive state,
(3)
This property of binding GDP and GTP is
what characterizes the entire family of
plasma-membrane and cytoplasmic G
proteins.
b)
Several features of the G-protein system help
explain how a single first messenger can initiate a
very complex cellular response.
(1)
There are at least 20 distinct plasmamembrane G proteins, and a single receptor
type may be associated with more than one
type of G protein.
(2)
Each of these G proteins may couple to
more than one type of the many plasmamembrane effector proteins. Thus, a
messenger-activated receptor, via its Gprotein couplings, can call into action a
variety of effector proteins, which in turn
induce a variety of cellular events.
2.
An Example: Gs Protein, Adenylyl Cyclase, and Cyclic AMP.
In this pathway, activation of the receptor (Figure 5-5) by the
binding of first messenger (for example, the hormone
epinephrine) allows the receptor to activate its associated G
protein, in this example known as Gs (the subscript s
denotes "stimulatory'). This causes Gs to activate its effector
protein, the membrane enzyme called adenylyl cyclase. The
activated adenylyl cyclase,
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Chapter 5 – Chemical Messengers
Human Physiology 135-152
a)
b)
c)
d)
Cyclic AMP was first second messenger - Done by
Earl W. Sutherland, Jr. who won Nobel Prize in 1971
for this work
Structure - Figure 5-6, page 144
Amplification - Figure 5-7, page 144
Binding can activate an enzyme called adenyl
cyclase via a Gs protein (s = stimulatory)
Deactivation  phosphodiesterase
Result is the production of cyclic AMP
The cAMP can then activate an inactive protein
kinase (cAMP-dependent protein kinase) - Figure 517, page 168
(1)
The nature of the enzymatic pathway that is
set in "motion" depends on the nature of the
protein kinase present in the cell - the
protein kinase may be free in the cytoplasm
or membrane bound such as Protein Kinase
C
(2)
That activated kinase then starts a
"cascade" effect
(3)
The net result is the response by the cell
h)
Can get activation and inhibition (Gi)
Phospholipase C, diacylglycerol and inositol trisphosphate
a)
The relevant G protein (termed Gq), activated by a
first-messenger-bound receptor, activates a plasmamembrane effector enzyme called phospholipase C.
(1)
This enzyme catalyzes the breakdown of a
plasma-membrane phospholipid known as
phosphatidylinositol bisphosphate,
abbreviated PIP2, to diacylglycerol (DAG)
and inositol trisphosphate (IP3) (Figure 5-9).
(2)
Both DAG and IP3 then function as second
messengers but in very different ways.
b)
DAG activates a particular protein kinase known as
protein kinase C, which then phosphorylates a large
number of other proteins, leading to the cell's
response.
c)
IP3, does not exert its second messenger role by
directly activating a protein kinase.
(1)
IP3, after entering the cytosol, binds to
calcium channels on the outer membranes
of the endoplasmic reticulum and opens
them.
(2)
Because the concentration of calcium is
much higher in the endoplasmic reticulum
than in the cytosol, calcium diffuses out of
this organelle into the cytosol
(3)
Increases cytosolic calcium concentration.
e)
f)
g)
3.
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Chapter 5 – Chemical Messengers
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(4)
F.
G.
H.
I.
J.
K.
This increased calcium concentration then
continues the sequence of events leading to
the cell's response to the first messenger
Control of ion channels by G Proteins
1.
Direct G-protein gating  shown in Figure 5-9
2.
Indirect G-protein gating  shown in Figure 5-9, works via a
second messenger (cAMP-dependent protein kinase)
Channel receptor activation influences  Table 5-3, page 146
1.
Ion channel or gate is part of the receptor
2.
G-protein directly gates the channel
3.
G-protein indirectly gates the channel (see above)
Calcium as a "second messenger" - Text page 147
1.
The cytosolic concentration of calcium ion can increase
dramatically upon certain stimuli
2.
What is the effect and how?
3.
How do some first messengers elicit a decrease in cytosolic
calcium ion concentration?
Most common mechanisms by which stimulation of a cell leads to
an increase in cytosolic Ca2+ concentration:
1.
Receptor activation
a)
Plasma-membrane calcium channels open in
response to a first messenger; the receptor itself
may contain the channel or the receptor may
activate a G protein that directly or indirectly opens
the channel.
b)
Calcium is released from the endoplasmic reticulum;
this is mediated by second messengers.
c)
Active calcium transport out of the cell is inhibited by
a second messenger.
2.
Opening of voltage-sensitive calcium channels
Major mechanisms by which an increase in cytosolic Ca2+
concentration induces the cell's responses:
1.
Calcium binds to calmodulin, Figure 5-10, page 147. On
binding calcium, the calmodulin changes shape, which
allows it to activate or inhibit a large variety of enzymes and
other proteins. Many of these enzymes are protein kinases.
2.
Calcium combines with calcium-binding intermediary
proteins other than calmodulin. These proteins then act in a
manner analogous to calmodulin.
3.
Calcium combines with and alters response proteins directly,
without the intermediation of any specific calcium-binding
protein.
4.
Calcium as second messenger summary table, Table 5-4,
page 147
Receptors and gene transcription
1.
First example given before with lipid soluble messengers
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Chapter 5 – Chemical Messengers
Human Physiology 135-152
2.
III.
There are many examples of plasma-membrane receptors
that eventually alter gene transcription via second
messengers
a)
Known as Primary Response Genes (PRG) aka
immediate-early genes
b)
A PRG may be a transcription factor for other genes,
Figure 5-20, page 171
c)
A hot area of research
L.
8. Eicosanoids
1.
Ubiquitous chemical messengers that include the related
compounds derived from the polyunsaturated fatty acid
arachidonic acid prostacyclins, thromboxanes and
leukotrienes (collectively it was acceptable to refer to this
group as prostaglandins but they are now known as
eicosaniods)
2.
All are unsaturated fatty acids with a carbon ring at one end
3.
Arachidonic acid is present in plasma-membrane
phospholipids
a)
Phospholipase A2 is stimulated in cell membrane
by messenger
b)
Splits off arachidonic acid which can then go one of
two ways via cyclooxygenase or lipoxygenase
4.
Classified by a letter PGA, PGE etc. - and by the number of
double bonds - PGE2.
5.
Prostaglandins fall into the category of paracrine agents and
specific examples will be discussed in other chapters
6.
Aspirin inhibits cyclooxygenase (nonsteroidal antiinflammatory drugs
Cessation of activity in signal
transduction pathways
a)
Key event is usually the cessation of receptor
activation
b)
Organic second messengers are rapidly inactivated
c)
A major way that receptor activation ceases is by a
decrease in the concentration of messenger
molecules in the region of the receptor
d)
The receptor becomes chemically altered (usually by
phosphorylation), which lowers its affinity for
messenger, and so the messenger is released
e)
Removal of plasma-membrane receptors occurs
when the combination of first messenger and
receptor is taken into the cell by endocytosis
Reference Table of Important Second Messengers, Table 5-5, page 150
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