Control of Cells by Chemical

Messengers
Lecturer: Ahmed Abu-zaitoon
 Receptors

• There are several classes of chemical

messengers; for example chemicals such as
neurotransmitters, whose signals are mediated
rapidly and over a short distance.
Also messengers, such as hormones, whose
signals are communicated more slowly and over
greater distances.
• The cell receiving the signal must have:
A means of detecting the signal's presence,
And then use a transduction mechanism to
convert that signal into a biologically
meaningful response (e.g., the cell-division
response to the delivery of growth-promoting
signals)
• First step: is the binding of the messenger to
specific target-cell proteins known as receptors
A chemical messenger is a "ligand," and the
receptor has a "binding site" for that ligand

• Second step: The binding of a messenger to a

receptor then initiates a sequence of events in
the cell leading to the cell's response to that
messenger, a process called signal
transduction.
• What is the nature of receptors?
They are proteins (or glycoproteins) located either
in the cell's plasma membrane or inside the cell,
mainly in the nucleus
 Signal Transduction Pathways

• Binding a chemical messenger leads to:

Activates a receptor, and this activation:
Initiates one or more signal transduction
pathways leading to the cell's response
1. Receptor activation:
 The combination of messenger with receptor causes a
change in the conformation (three-dimensional shape) of the
receptor. This event, known as receptor activation
 This step always the initial step leading to the cell's ultimate
responses to the messenger.

• These responses can take the form of changes in:

(1) The permeability, transport properties, or electrical state of
the cell's plasma membrane;
(2) The cell's metabolism;
(3) The cell's secretory activity;
(4) The cell's rate of proliferation and differentiation; and
(5) The cell's contractile activity.
• Despite the seeming variety of these five types
of ultimate responses, there is a common
denominator: They are all directly due to
alterations of particular cell proteins.
e.g. The neurotransmitter-induced generation of
electrical signals in nerve cells reflects the altered
conformation of membrane proteins (ion channels)
through which ions can diffuse between
extracellular fluid and intracellular fluid.
e.g. Changes in the rate of glucose secretion by the
liver induced by epinephrine reflect the altered
activity and concentration of enzymes in the
metabolic pathways for glucose synthesis.
2. Signal transduction pathways:
• The sequences of events between receptor
activation and the responses are diverse and
are termed signal transduction pathways.
• Signal transduction pathways differ between
lipid-soluble and lipid-insoluble messengers in
which there receptors found in different
locations.
For lipid-soluble messengers the receptors found
inside the cell
For lipid-insoluble messengers the receptors found
in the plasma membrane of the cell
1) Pathways Initiated by Intracellular Receptors:

• Most lipid-soluble messengers are hormones

(steroid hormones), the thyroid hormones, and
the steroid derivative, 1,25-dihydroxy-vitamin D.
• The receptors are intracellular and are inactive
when no messenger is bound to them.
• Most of the inactive receptors in the steroid
hormone superfamily already reside in the cell
nucleus, where they bind to and are activated
by their respective ligands
• In a few cases, the inactive receptors are
located in the cytosol and move into the
nucleus after binding their hormone.
• Receptor activation leads to altered rates of
gene transcription.
• Because of their lipid solubility, steroids and
thyroid hormones exist in blood in two forms
A small fraction of these messengers is dissolved
freely in plasma, in equilibrium with:
A larger fraction that is bound to a circulating
binding protein.
• Binding proteins increase the quantity of lipid-soluble
messengers that can be carried by the blood at any
one time
• Steps:
1. The unbound messenger diffuses from the plasma across the cell's
plasma membrane and nuclear membrane to enter the nucleus and
bind to the receptor there.
2. The receptor, activated by the binding of hormone to it, then
functions in the nucleus as a transcription factor, defined as any
regulatory protein that directly influences gene transcription.
3. The hormone-receptor complex binds to a specific sequence near a
gene in DNA, termed a response element, an event that increases
the rate of that gene's transcription into mRNA.
4. The mRNA molecules formed subsequently move out of the
nucleus to direct the synthesis, on ribosomes, of the protein
encoded by the gene.
5. The result is an increase in the cellular concentration of the pro­tein
and/or its rate of secretion, and this accounts for the cell's ultimate
response to the messenger
• Two important points must take in
consideration:
First, more than one gene may be subject to
control by a single receptor type.
Second, in some cases the transcription of the
gene(s) is decreased by the activated receptor
rather than increased.
2) Pathways Initiated by Plasma Membrane
Receptors:
• On the basis of the signal transduction pathways they initiate,
plasma membrane receptors can be classified into the types
listed in the following table:
• Three general terminologies related to this
pathway:
1. The intercellular chemical messengers that
reach the cell from the extracellular fluid and
bind to their specific receptors are often
referred to as first messengers.
2. Second messengers, then, are substances
that enter or are generated in the cytoplasm
as a result of receptor activation by the first
messenger.
 The second messengers diffuse throughout the
cell to serve as chemical relays from the plasma
membrane to the biochemical machinery inside
the cell
3. Protein kinase: protein kinase is the name for
any enzyme that phosphorylates other
proteins by transferring to them a phosphate
group from ATP.
 Introduction of the phosphate group changes the
conformation and/or activity of the recipient
protein, often itself an enzyme
 There are many different protein kinases, each
type being able to phosphorylate only certain
proteins
• A variety of protein kinases are involved in
signal transduction pathways.
These pathways may involve a series of reactions
in which a particular inactive protein kinase is
activated by phosphorylation and then catalyses the
phosphorylation of another inactive protein kinase,
and so on.
At the ends of these sequences, the ultimate
phosphorylation of key proteins (transporters,
metabolic enzymes, ion channels, contractile
proteins, and so on) underlies the cell's biochemical
response to the first messenger
• Other enzymes do the reverse of protein
kinases; that is, they dephosphorylate proteins.
These enzymes, termed protein phosphatases,
also participate in signal transduction pathways
a. Receptors that Function as Ion Channels

• The protein that acts as the receptor itself

constitutes an ion channel
• Activation of the receptor by a first messenger
causes the channel to open.
• The opening results in an increase in the net
diffusion across the plasma membrane of the
ion or ions specific to the channel.
• Such a change in ion diffusion is usually
associated with a change in the membrane
potential.
This electrical signal is often the essential event in
the cell's response to the messenger.
• When the channel is a calcium channel, its
opening results in an increase, by diffusion, in
the cytosolic calcium concentration.
Increasing cytosolic calcium is another essential
event in the transduction pathway for many
signaling systems