INTRODUCTION TO CELL SIGNALLING

Academic Script
1. Introduction
In this lesson, we will look at signal transduction in
animals. Conversation in the biological world is quite
natural. Even on the level of the cell, a busy broadcast
of communications is occurring.

Signal transduction is the study of how a cell

communicates. Every cell is able to communicate
through having evolved the ability to produce,
recognize, interpret and respond to signals in its
environment. The word ‘signals’ in this context refers
to nothing more than chemical molecules that are
floating around. Cells have learned to detect many of
these chemicals. Their molecular detection
components—produced by the genes they contain—
allow the cells to converse in this chemical “language
of the cell.”

When you come right down to it, this ability to

communicate has allowed cells to evolve. If a cell
could not receive or respond to signals from its
environment, for example sensing food or predators, it
would be unable to adapt its behavior, and over time,
would be out competed by those that could
communicate. Therefore, it does form a vital part of a
cell.

Where did the term “Signal Transduction” Originate

from?

The term signal transduction is an umbrella term in

biology. It is used to refer to a broad area of cellular
biology research involving topics such as the chemical
signals used by cells, how these signals are received,
how a cell interprets them, and the ways in which
cellular machinery can be used to respond .

Essentially signal transduction ensures that a message

can be converted from one form to another during its
travels and still retain its original content. Let’s look at
human communication as an illustration. Consider how
a message is sent over the telephone: one person
speaks into a receiver that converts the sound into an
electrical signal, which can then be transmitted over
great distances before being converted back into
sound at its destination. This process retains the
original content of the message and is called signal
transduction.

The signals sent by cells are far simpler than the

highly complex messages used by humans. One cell—
termed the signaling cell—produces a particular
chemical molecule that is detected by another cell—
 the receiving cell—using a receptor protein that
recognizes the molecule and responds specifically to
it. The protein, acting as the receptor, is the first step
in which the chemical signal present on the outside of
the cell will be converted (transduced) to different
signals inside the cell. These signals will subsequently
direct cell behavior.

Multicellular organisms have developed a variety of

mechanisms allowing very efficient and controlled cell-
to-cell communication.. Depending on the distance
that the signaling molecule has to travel, we can talk
about following types of signaling:

1. Endocrine signaling
Here hormones are produced by an endocrine gland
and sent through the blood stream to distant cells.

2. Paracrine signaling
Here the signalling molecule affects only target cells in
the proximity of the signaling cell. An example is the
conduction of an electric signal from one nerve cell to
another or to a muscle cell.

3. Autocrine signaling
In autocrine signaling cells respond to molecules they
produce themselves. Examples include many growth
factors.
4. Signaling by the plasma membrane attached
protein
The proteins attached to the plasma membrane of one
cell could interact directly with receptors to an
adjacent cell.

5. Neuro-endocrine signaling
The neuro-secretory neurons of hypothalamus
produce neuro-secretory hormone the releasing
factors, which act as signaling molecules for pituitary
which secretes its own hormones.

6. Signaling via gap junction

The gap junctions are specialized cell-cell junctions
formed between closely apposed plasma membranes
and which directly connect the cytoplasms of the cells
via narrow channels. These channels allow the
exchange of small intracellular signaling molecules or
mediators such as calcium and C-AMP but not
macromolecules. Hence these cells can communicate
with each other via gap junctions.

The list of signals that have been discovered numbers

in the hundreds and grows longer every day. Some
examples include proteins, peptides, amino acids,
 nucleotides, steroids, and gases. Molecular signals
sent by one cell is processed and converted into
response by series of steps via signal transduction.
Most signalling molecules (eg. protein hormones)
targeted to a cell bind at the cell surface receptors
embedded in plasma membrane. Signalling molecules
that are able to cross plama membrane (eg. Steroid
hormones) interact with intracellular receptors. Hence
according to nature of signalling molecule,there are
two different pathways for signal transduction. They
are signal transduction for protein hormone and signal
transduction for steroid hormones. Other signaling
molecules are neurotransmitters, growth factors,
cytokines, Nitric Oxide (NO), Dopamine, etc.

2. Signal Transduction for Protein Hormones

In 1971, Martin Rodbell and his co-workers working
on rat liver cells found that a GTP binding regulatory
protein called G-protein activates adenylatecyclase.
Thus Sutherland’s cascade phenomenon is modified.
 A Protein hormone secreted by an endocrine gland
travels via the blood stream to deliver a signal to a
target cell.
 Small molecule, peptide, and protein hormones are
hydrophilic and can not cross the membrane barrier of
the target cell. So hormone binding to trans-
membrane protein receptors transduces the signal
 across the cell membrane that produces a cellular
response.

 The hormone membrane receptor is a large protein

that consists of seven, hydrophobic trans-membrane-
spanning regions. The free N- (amino) terminus of the
receptor protein is external to the cell, and the free C-
(carboxyl) terminus is internal.
 The receptor is associated with the G-protein. G-
protein receptor comprises of α, β and γ sub units.
 The peptide hormone assumes its active configuration
as it approaches the extra-cellular active site of the
receptor, thereby locking into the active site and
transferring its information.
 The information transferred to the interior of the cell
results in a mechanical interaction between the
receptor and a G-protein.
 Mechanically activation of G-protein results in a
transfer of a guanosinetrisphosphate (GTP)
for guanosinediphosphate (GDP) on the α-sub unit.
 The GTP activates the α-sub unit, which separates
from the β and γ sub units and interacts with an
inactive adenylyl cyclase within the plasma
membrane, stimulating the synthesis of Cyclic AMP
i.e., second messenger. cAMP activates protein
Kinases A (Kinases are enzymes that transfer a
phosphate from ATP to other proteins i.e. bring about
 phosphorylation). cAMP is inactivated by
phosphodiesterase in the cell.
 The α sub unit is a slow GTPase, and thus the GTP is
hydrolyzed to GDP after a period of time.
The α subunit then reassociates with
the β and γ subunits and the adenylcyclase is
inactivated.
 Protein Kinase A has 2 catalytic subunits and 2
regulatory subunits. Attachment of regulatory subunit
to catalytic portion makes protein Kinase A inactive.
 When cAMP binds to the regulatory subunits, the
tetramer releases its two active catalytic subunits.

 Active Catalytic subunits pick up energy from ATP and

then act on enzyme in the cell, i.e., phosphorylases
and activate it.
 Glycogen phosphorylase is responsible for
glycogenolysis - the breakdown of glycogen to
glucose.
 Protein Kinase A initiates a signal transduction
cascade that results in the intracellular breakdown of
glycogen to glucose in case of Adrenaline as a
hormone. The net result is increased muscle energy.
Thus, activation of surface receptors “switches on” the
activity of other intracellular signaling proteins. In
turn, these proteins activate other proteins in a series
of events called as signal cascade. Because of this
cascade, signal transduction is very useful in
conducting a fast response. In each step the original
hormone(i.e.,signal) is amplified and since the method
uses the little amount of hormone to create a large
effect, the body does not need to waste time and
energy producing a lot of that hormone.

Second messenger
Earl Wilbur Sutherland, Jr., discovered second
messengers, for which he won Nobel Prize in 1971 in
Physiology. Second messengers are small molecules
or ions, such as nucleotide or lipid derivatives, which
elicit changes in a metabolic pathway some distance
away from the membrane. They greatly amplify the
strength of the signal. e.g. Cyclic AMP, Calcium,
Lipids, , Inositol Triphosphate , Diacylglycerol , nitric
oxide and Free radicals. Secondary messenger
systems can be synthesized and activated by
enzymes, like the cyclases that synthesize cyclic
nucleotides, or by opening of ion channels to allow
influx of metal ions, like calcium signaling. These
small molecules bind and activate protein kinases, ion
channels, and other proteins, thus continuing the
signaling cascade. Secondary messengers are a
component of signal transduction cascades.Their
production and destruction can be localized, enabling
the cell to limit space and time of signalling activity.
 G-proteins
 G-proteins (guanine nucleotide-binding proteins) are a
family of proteins involved in transmitting chemical
signals outside the cell, and causing changes inside
the cell. They communicate signals from many
hormones, neurotransmitters, and other signaling
factors.
 G-protein is a heterotrimer, it has got 3 subunits, α, β
and γ subunits. β and γ are alike and occur as
dimmers. Most important is α -subunit which is
different from others.
 All G-proteins except Gp and Ras proteins are
heterotrimers.
 It is GTP binding regulatory protein or Guanine
nucleotide binding regulatory protein, which may be of
inhibitory or stimulatory type.
 They are widely distributed and unique to eukaryotic
cells and are involved in the responses produced by
functionally different numerous receptor types, such
as ion channels in the nerve and muscle cells,
hormone receptors in all types of cells and photon
receptors in the visual system.
Earl Sutherland and Martin Rodbell have described the
mechanism of action of protein hormones. Rodbell’s
important discovery of G-proteins and cell signaling
has paved the way in understanding the occurrence of
 several disorders associated with defects either in the
G-protein itself or in its receptor.

Human diseases due to defected G-protein

These are Pituitary thyroid tumours, Combined

precocious puberty and pseudo-hypoparathyroidism,
McCune-Albright syndrome,which causes due to
defective G-Protein ( i.eGsα).And next is
Adrenocortical ovarian tumours,Which is due to
defective G-Protein (Giα).

Human diseases due to defective G-protein

receptor
First one is Hyperthyroidism it is due to Defective G-
Protein Receptor i.e TSH receptor. Next is Retinitis
pigmentosa which is due to defective Rhodopsin
receptor. Next one is Familial glucocorticoid
deficiency which causes due to defective ACTH
receptor.

Recycling of protein hormone receptor

 Most of the protein hormones bind to membrane
receptors to elicit their actions. After binding the
hormone receptor complex is metabolized. This
process helps to terminate the signal leading to bring
about hormone action.
 Receptor with ligand aggregated and after
aggregation, the pits bud of (i.e.,endocytosis). After
endocytosis, it quickly loss their clathrin coat, clathrin
coat is important for endocytosis and for forming
CURL (Compartment for Uncoupling Receptor and
Ligand), i.e., receptosome.
 Receptosome acidification using ATP molecule and due
to this there is separation of ligand and receptor in
such a way that ligand remain in vesicle and receptor
remains in the extended tubule.
 Extended tubules are able to move towards Golgi
apparatus and their they fuse with Golgi apparatus.

 Modification of receptor occurs in Golgi apparatus and

then this receptor is moved from the Golgi in the form
of vesicle to PM and by exocytosis this receptor
remains on PM. In this way receptor is ready to
receive another ligand.
 And ligand fuse with 2nd lysosome where lysosomal
enzyme breaks the ligand and makes it inactive and
exocytosis occurs.
 In this way Protein hormone receptor is recycled.

3. Signal Transduction for Steroid Hormones

Steroid hormones are essential regulators of key
physiological processes such as reproduction, glucose
metabolism, and the response to stress and salt
balance. The biological effects of steroid hormones are
transduced by intracellular receptors that directly
mediate the action of their cognate hormone.
Unlike Protein hormone, however most hydrophobic
signaling molecules can diffuse across the plasma
membrane and bind to receptors inside the target cell
in the cytoplasm or nucleus. Steroid hormones are
one such example.
Steroid hormones are smaller and hydrophobic
molecules that binds to intracellular receptors in the
target tissue to elicit its action.
The steroid hormones are C18, C19 and C21 compounds
produced by the gonads, adrenal cortex and placenta.

Mechanism of steroid hormone action

As soon as the steroid enters the cell and binds to the
receptor component of the receptor-protein complex
causing dissociation, release of Heat Shock Proteins
(HSP) and activation of receptor. The activated
receptor develops an affinity for DNA and translocated
from cytosol to nucleus where it binds to DNA
segment. The DNA binding results in a change in the
transcriptional rate of specific gene(s). The resulting
production of more or less mRNA under the control of
transcription factors and RNA polymerase leads to
changes in the contents of the specific proteins in the
target cell.
 Properties of nuclear receptor
 Receptors for steroid hormones are known as nuclear
receptor as they are located inside the nucleus of the
target cell. Receptors located in nucleus are active and
small in size while those located in cytoplasm are
inactive and larger in size All are proteinaceous in
nature and are heat sensitive.
 They are present in cytoplasm in the form of
homodimers attached with heat shock protein (HSP),
i.e. steroid receptors exist intra-cellularly as
homodimers with a non-steroid binding HSP.
 The nuclear receptor would recognize the signal
(steroid hormone) and transducer its biological effect.
 The receptors belong to super-family proteins, all of
which are regulators of gene transcription.
 The super-family consists of the receptor for steroid
hormones, thyroid hormones, vitamin D3 and retinoic
acid.
 Members of this family share 3 important properties.
They each bind a hormone ligand, & further bind to
specific DNA sequence and thereby they act to modify
the transcription activity of specific gene(s).
 All steroid receptor has similarity and are considered
as prototype receptor, it have 3 domains, which are
Amino terminal domain, Central Domain, i.e. DNA
binding domain, Carboxy terminal end region or
Ligand binding domain.

Recycling of steroid hormone receptor

The fate of steroid-receptor complexes after their
nuclear retention in target cells is not firmly
established. Nuclear glucocorticoid- and androgen-
receptor complexes could be recycled back to the
cytosol in their responsive tissues, whereas this has
not been clearly established for the case of
progesterone and estrogen receptors. The models of
steroid receptor recycling proposed so far involve
release of chromatin-bound complexes into the
cytosol, loss of steroid, and receptor inactivation.
These receptors, however, can eventually be
reactivated to a steroid binding form to reinitiate a
cycle of steroid binding and further nuclear
translocation. We propose that this model can
represent a general aspect of steroid hormone action,
provided that inactivation or reactivation processes
occur in every steroid responsive system. A process
involving a reversible receptor inactivation could play
a major role in the control of steroid receptor
recycling. It is proposed that a control on the extent of
receptor available to steroid binding could result in a
modulation of cellular responses to steroid hormones.
4. Summary
At the end to conclude, this lesson described process
of cell signaling, types of cell signaling found in
different cells, signal transduction and their
importance. Signal Transduction further follows it for
Protein Hormones. Further the lesson explores note on
second messenger and G-Proteins. Rodbell’s important
discovery of G-Proteins and cell signaling has paved
the way in understanding the occurrence of several
disorders associated with defects either in G-Protein
itself or in its receptor has also been discussed. Lastly,
Signal transduction for steroid hormones and note on
nuclear receptor and it’s recycling has been
mentioned. Thus in this manner complete signal
transduction in animals has been studied.