Second messenger and signal transduction pathways Calcium pathway , Receptor, Ligand, G- protein, cAMP pathway

1. Signal Transduction

2. Signal Transduction
Defination : Signal transduction is the process by which a chemical or
physical signal is transmitted through a cell as a series of molecular events, most
commonly protein phosphorylation, which ultimately result in a response.
Proteins responsible for detecting stimuli are generally termed receptors,
although in some cases the term sensor is used.
Receptor : Proteins responsible for detecting stimuli are
generally termed receptors, although in some cases the term
sensor is used
Ligand : The extracellular messenger that binds to the
receptor Protein on cell membrane is called ligand.

3. Signal transduction Pathway
• Defination : A set of chemical reactions in a cell that occurs when a molecule,
such as a hormone, attaches to a receptor on the cell membrane. The pathway is
actually a cascade of biochemical reactions inside the cell that eventually reach
the target molecule or reaction.
• Cell Signaling stages : Cell signaling can be divided into 3 stages.
1) Reception: A cell detects a signaling molecule from the outside of
the cell.
2) Transduction: When the signaling molecule binds the receptor it
changes the receptor protein in some way.
3) Response: Finally, the signal triggers a specific cellular response.

4. Reception:
• It is done by Membrane receptors function by binding the signal molecule (ligand) and
causing the production of a second signal (also known as a second messenger) that then
causes a cellular response. These type of receptors transmit information from the
extracellular environment to the inside of the cell by changing shape or by joining with
another protein once a specific ligand binds to it. Examples of membrane receptors
include G Protein-Coupled Receptors and Receptor Tyrosine Kinases.
• Intracellular receptors are found inside the cell, either in the cytoplasm or in the nucleus
of the target cell (the cell receiving the signal). Chemical messengers that are very small
(steroid hormones for example) can pass through the plasma membrane without
assistance and bind these intracellular receptors. Once bound and activated by the
signal molecule, the activated receptor can initiate a cellular response, such as a change
in gene expression. Receptor for Nitric oxide is intramolecular receptor which when
receives ligand enters nucleus and act as transcription factor.
• Most signaling molecules are too large /or hydrophobic to get through the cell
membrane, hence the need for protein receptors on the receiving cell’s
membrane. Receptors are usually integral membrane proteins and the binding site is
usually located in the strictly extracellular portion but is sometimes in the membrane
spanning domain

5. Transduction
• Steps in the signal transduction pathway often involve the addition or
removal of phosphate groups which results in the activation of proteins.
Enzymes that transfer phosphate groups from ATP to a protein are called
protein kinases. Many of the relay molecules in a signal transduction
pathway are protein kinases and often act on other protein kinases in the
pathway. Often this creates a phosphorylation cascade, where one enzyme
phosphorylates another, which then phosphorylates another protein,
causing a chain reaction.
• Protein phosphatases are enzymes that can rapidly remove phosphate
groups from proteins (de-phosphorylation) and thus inactivate protein
kinases. Protein phosphatases are the “off switch” in the signal
transduction pathway.

6. Response :
• Cell signaling ultimately leads to the regulation of one or more cellular
activities. Regulation of gene expression (turning transcription of specific genes
on or off) is a common outcome of cell signaling. A signaling pathway may also
regulate the activity of a protein, for example opening or closing an ion channel
in the plasma membrane or promoting a change in cell metabolism such as
catalyzing the breakdown of glycogen. Signaling pathways can also lead to
important cellular events such as cell division or apoptosis (programmed cell
death).

7. Forms of signaling
• There are four basic categories of chemical signaling found in multicellular
organisms:
• paracrine signaling,
• autocrine signaling,
• endocrine signaling, and
• signaling by direct contact.
• The main difference between the different categories of signaling is the
distance that the signal travels through the organism to reach the target cell.

8. Paracrine signaling
• Often, cells that are near one another communicate through the release of
chemical messengers (ligands that can diffuse through the space between the
cells). This type of signaling, in which cells communicate over relatively short
distances, is known as paracrine signaling.
Paracrine signaling allows cells to locally coordinate activities with their neighbors.
Although they're used in many different tissues , paracrine signals are especially
important during development, when they allow one group of cells to tell a
neighboring group of cells what cellular identity to take on.

9. Synaptic signaling
• One unique example of paracrine signaling is synaptic signaling, in which nerve
cells transmit signals. This process is named for the synapse, the junction
between two nerve cells where signal transmission occurs.
• When the sending neuron fires, an electrical impulse moves rapidly through the
cell, traveling down a long, fiber-like extension called an axon. When the impulse
reaches the synapse, it triggers the release of ligands called neurotransmitters,
which quickly cross the small gap between the nerve cells.
• When the neurotransmitters arrive at the receiving cell, they bind to receptors
and cause a chemical change inside of the cell (often, opening ion channels and
changing the electrical potential across the membrane).

10. Autocrine signaling
• In autocrine signaling, a cell signals to itself, releasing a ligand that binds to
receptors on its own surface (or, depending on the type of signal, to receptors
inside of the cell). This may seem like an odd thing for a cell to do, but autocrine
signaling plays an important role in many processes.
• For instance, autocrine signaling is important during development, helping cells
take on and reinforce their correct identities. From a medical standpoint,
autocrine signaling is important in cancer and is thought to play a key role in
metastasis (the spread of cancer from its original site to other parts of the
body).

11. Endocrine signaling
• When cells need to transmit signals over long distances, they often use the
circulatory system as a distribution network for the messages they send. In
long-distance endocrine signaling, signals are produced by specialized cells
and released into the bloodstream, which carries them to target cells in distant
parts of the body. Signals that are produced in one part of the body and travel
through the circulation to reach far-away targets are known as hormones.
• In humans, endocrine glands that release hormones include the thyroid, the
hypothalamus, and the pituitary, as well as the gonads (testes and ovaries) and
the pancreas. Each endocrine gland releases one or more types of hormones,
many of which are master regulators of development and physiology.

12. Signaling through cell-cell contact
• Gap junctions in animals and plasmodesmata in plants are tiny channels that directly
connect neighboring cells. These water-filled channels allow small signaling
molecules, called intracellular mediators, to diffuse between the two cells. Small
molecules, such as calcium ions are able to move between cells, but large molecules
like proteins and DNA cannot fit through the channels without special assistance.
• The transfer of signaling molecules transmits the current state of one cell to its
neighbor. This allows a group of cells to coordinate their response to a signal that only
one of them may have received. In plants, there are plasmodesmata between almost
all cells, making the entire plant into one giant network.

13. Major pathways of signal transduction
• Following are some major signaling pathways, demonstrating how ligands binding to their receptors can
affect second messengers and eventually result in altered cellular responses.
• MAPK/ERK pathway Mitogen-activated protein kinases / Extracellular Signal-Regulated Kinase :
• A pathway that couples intracellular responses to the binding of growth
factors to cell surface receptors. This pathway is very complex and includes
many protein components. In many cell types, activation of this pathway promotes cell division, and
many forms of cancer are associated with aberrations in it.
• cAMP-dependent pathway: In humans, cAMP works by activating protein kinase A (PKA, cAMP-
dependent protein kinase) , and, thus, further effects depend mainly on cAMP-dependent protein kinase,
which vary based on the type of cell.
• IP3/DAG pathway: Inositol trisphosphate / diacylglycerol
• PLC (phospho-lipase C) cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2),
yielding diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG remains bound to the
membrane, and IP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the
cytosol to bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). These
channels are specific to calcium and allow the passage of only calcium to move through. This causes the
cytosolic concentration of Calcium to increase, causing a cascade of intracellular changes and
activity.[55] In addition, calcium and DAG together works to activate PKC, which goes on to phosphorylate
other molecules, leading to altered cellular activity. End-effects include taste, manic depression, tumor
promotion, etc.

14. Steps in signal transduction:
• Synthesis of signaling molecule by signaling cell (e.g. hormones by pituitary
gland)
• Release of signaling molecule (e.g. into blood or extracellular matrix)
• Transport to receiving cell (e.g. in blood)
• Binding to receptor
• Initiation of intracellular signal transduction
• Resultant changes to cellular functions functions (e.g. activating enzymes would
be a fast response, changing gene expression would be a slower response)
• Feedback regulation: removal of signaling molecule or disabling of receptor (e.g.
via endocytosis).

15. Mechanism
1. Synthesis of signaling molecule by signaling cell (e.g. hormones by pituitary
gland)
Synthesis of signaling molecule by signaling cell (e.g. hormones by pituitary gland) takes
place first to initiate cell signaling.
2. Release of signaling molecule (e.g. into blood or extracellular
matrix)
Release of signaling molecule (e.g. into blood or extracellular matrix) is released into
blood or outside cell to reach the target cell.
3. Transport to receiving cell (e.g. in blood)
Blood takes that molecule or hormone and transports it to it’s target cell while
performing the action of circulation in the body.

16. 4.Binding of Ligand
• When a ligand binds to a cell-surface receptor, the receptor’s intracellular domain (part
inside the cell) changes in some way. Generally, it takes on a new shape, which may make it
active as an enzyme or let it bind other molecules.
• The change in the receptor sets off a series of signaling events. For instance, the receptor
may turn on another signaling molecule inside of the cell, which in turn activates its own
target. This chain reaction can eventually lead to a change in the cell's behavior or
characteristics
• Because of the directional flow of information, the term upstream is often used to describe
molecules and events that come earlier in the relay chain, while downstream may be used
to describe those that come later (relative to a particular molecule of interest). For instance,
in the diagram, the receptor is downstream of the ligand but upstream of the the proteins in
the cytosol. Many signal transduction pathways amplify the initial signal, so that one
molecule of ligand can lead to the activation of many molecules of a downstream target.
• The molecules that relay a signal are often proteins. However, non-protein molecules like
ions and phospholipids can also play important roles.

18. Phosphorylation.
• Proteins can be activated or inactivated in a variety of ways. However, one of the most
common tricks for altering protein activity is the addition of a phosphate group to
one or more sites on the protein, a process called phosphorylation.
• Phosphate groups can’t be attached to just any part of a protein. Instead, they are
typically linked to one of the three amino acids that have hydroxyl (-OH) groups in
their side chains: tyrosine, threonine, and serine. The transfer of the phosphate group
is catalyzed by an enzyme called a kinase, and cells contain many different kinases
that phosphorylate different targets.
• Phosphorylation often acts as a switch, but its effects vary among proteins.
Sometimes, phosphorylation will make a protein more active (for instance, increasing
catalysis or letting it bind to a partner). In other cases, phosphorylation may
inactivate the protein or cause it to be broken down.

19. • In general, phosphorylation isn’t permanent. To flip proteins back into their non-
phosphorylated state, cells have enzymes called phosphatases, which remove a
phosphate group from their targets.

20. 2.Phosphorylation example: MAPK
signaling cascade
• To get a better sense of how phosphorylation works, let’s examine a real-life
example of a signaling pathway that uses this technique: growth factor signaling.
Specifically, we'll look at part of the epidermal growth factor (EGF) pathway that acts
through a series of kinases to produce a cellular response.

22. • Phosphorylation (marked as a P) is important at many stages of this pathway.
• When growth factor ligands bind to their receptors, the receptors pair up and act as kinases,
attaching phosphate groups to one another’s intracellular tails.
• The activated receptors trigger a series of events (skipped here because they don't involve
phosphorylation). These events activate the kinase Raf.
• Active Raf phosphorylates and activates MEK, which phosphorylates and activates the ERKs.
• The ERKs phosphorylate and activate a variety of target molecules. These include transcription
factors, like c-Myc, as well as cytoplasmic targets. The activated targets promote cell growth and
division.
• Together, Raf, MEK, and the ERKs make up a three-tiered kinase signaling pathway called
a mitogen-activated protein kinase (MAPK) cascade. (A mitogen is a signal that causes cells to
undergo mitosis, or divide.) Because they play a central role in promoting cell division, the genes
encoding the growth factor receptor, Raf, and c-Myc are all proto-oncogenes, meaning that
overactive forms of these proteins are associated with cancer^11start superscript, 1, end
superscript.
• MAP kinase signaling pathways are widespread in biology: they are found in a wide range of
organisms, from humans to yeast to plants. The similarity of MAPK cascades in diverse organisms
suggests that this pathway emerged early in the evolutionary history of life and was already
present in a common ancestor of modern-day animals, plants, and fungi^22squared
•

23. Second messengers :
• Small, non-protein, water-soluble molecules or ions called second messengers
(the ligand that binds the receptor is the first messenger) can also relay signals
received by receptors on the cell surface to target molecules in the cytoplasm or
the nucleus.
• Examples of second messengers include cyclic AMP (cAMP) and calcium ions,
cyclic GMP ,inositol triphosphate etc but most known is cAMP.
• The calcium ion Ca2+ has a critical role in the rapid responses of neurons and
muscle cells

24. Function of second messengers :
• As soon as Ligand binds to G receptor protein in cell membranes, G-
protein activation stimulates cAMP synthesis by adenylyl cyclase. The
newly synthesized cAMP is then able to act as a second messenger, rapidly
propagating the epinephrine signal to the appropriate molecules in the
cell. This stimulatory signaling pathway leads to the production of effects
such as increasing rate and force of contraction of the heart that are
characteristic of epinephrine. Caffeine also enhances the action of cAMP
by inhibiting the enzyme phosphodiesterase, which degrades cAMP; the
enhancement of cAMP activity contributes to the general stimulatory
action of caffeine. As a gas, nitric oxide (NO) is distinct among second
messengers in being able to diffuse across cell membranes, which allows
signal information to cross into neighbouring cells.

25. Calcium ions pathway
• Calcium ions are a widely used type of second messenger. In most cells, the
concentration of calcium ions in the cytosol is very low, as ion pumps in the
plasma membrane continually work to remove it. For signaling may be stored in
compartments such as the endoplasmic reticulum.
• Pathway:
• In pathways that use calcium ions as a second messenger, upstream signaling
events release a ligand that binds to and opens ligand-gated calcium ion channels
• .These channels open and allow the higher levels of that are present outside the
cell (or in intracellular storage compartments) to flow into the cytoplasm, raising
the concentration of cytoplasmic calcium ion.

26. Calcium ions pathway

27. • How does the released of calcium ion help pass along the signal?
Some proteins in the cell have binding sites for ions, and the released ions attach
to these proteins and change their shape (and thus, their activity). The proteins
present and the response produced are different in different types of cells. For
instance, calcium ion signaling in the β-cells of the pancreas leads to the release
of insulin, while calcium ion signaling in muscle cells leads to muscle contraction

28. Cyclic AMP (cAMP)
• Cyclic adenosine monophosphate (cyclic AMP or cAMP), is a small
molecule made from ATP used in many cells for signaling. In response to
signals, an enzyme called adenylyl cyclase converts ATP into cAMP,
removing two phosphates and linking the remaining phosphate to the sugar
in a ring shape.
• Pathway:
• In pathways that uses cyclic AMP, once generated, cAMP can activate an
enzyme called protein kinase A (PKA), enabling it to phosphorylate its
targets and pass along the signal. Protein kinase A is found in a variety of
types of cells, and it has different target proteins in each. This allows the
same cAMP second messenger to produce different responses in different
contexts.
• cAMP signaling is turned off by enzymes called phosphodiesterases, which
break the ring of cAMP and turn it into adenosine monophosphate (AMP).

29. Cyclic AMP (cAMP) pathway

30. Cellular response
• Despite these differences, signaling pathways share a common goal: to produce
some kind of cellular response. That is, a signal is released by the sending cell in
order to make the receiving cell change in a particular way.
• In some cases, we can describe a cellular response at both the molecular level
and the macroscopic (large-scale, or visible) level.
• At the molecular level, we can see changes such as an increase in the
transcription of certain genes or the activity of particular enzymes.
• At the macroscopic level, we may be able to see changes in the outward
behavior or appearance of the cell, such as cell growth or cell death, that are
caused by the molecular changes.
•

31. Gene expression
• Many signaling pathways cause a cellular response that involves a change in
gene expression. Gene expression is the process in which information from a
gene is used by the cell to produce a functional product, typically a protein. It
involves two major steps, transcription and translation.
• Transcription makes an RNA transcript (copy) of a gene's DNA sequence.
• Translation reads information from the RNA and uses it to make a protein.

32. Cellular metabolism
• Some signaling pathways produce a metabolic response, in which metabolic
enzymes in the cell become more or less active. We can see how this works by
considering adrenaline signaling in muscle cells. Adrenaline, also known as
epinephrine, is a hormone (produced by the adrenal gland) that readies the
body for short-term emergencies.
• When epinephrine binds to its receptor on a muscle cell (a type of G protein-
coupled receptor, it triggers a signal transduction cascade involving production
of the second messenger molecule cyclic AMP (cAMP). This cascade leads to
phosphorylation of two metabolic enzymes— that is, addition of a phosphate
group, causing a change in the enzymes' behavior.

34. Apoptosis
• When a cell is damaged, unneeded, or potentially dangerous to an organism,
it may undergo programmed cell death, or apoptosis. Apoptosis allows a
cell to die in a controlled manner that prevents the release of potentially
damaging molecules from inside the cell.
• Internal signals (such as those triggered by damaged DNA) can lead to
apoptosis, but so can signals from outside the cell. For example, most animal
cells have receptors that interact with the extracellular matrix, a supportive
network of proteins and carbohydrates. If the cell moves away from the
extracellular matrix, signaling through these receptors stops, and the cell
undergoes apoptosis. This system keeps cells from traveling through the
body and proliferating out of control (and is "broken" in cancer cells that
metastasize, or spread to new sites).

35. • Apoptosis is also essential for normal embryological development. In
vertebrates, for example, early stages of development include the formation
of tissue between what will become individual fingers and toes. During the
course of normal development, these unneeded cells must be eliminated,
enabling fully separated fingers and toes to form. A cell signaling mechanism
triggers apoptosis, which destroys the cells between the developing digits.

36. Refrences
• Bradshaw, Ralph A.; Dennis, Edward A., eds. (2010). Handbook of Cell Signaling (2nd
ed.). Amsterdam, Netherlands: Academic Press. ISBN 9780123741455.
• https://www.cureffi.org/2013/04/16/cell-biology-09-signal-transduction/
• https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of-cell-
signaling/a/introduction-to-cell-signaling
• https://www.sciencedirect.com/topics/medicine-and-dentistry/signal-transduction-
pathway
• Krauss, Gerhard (2008). Biochemistry of Signal Transduction and Regulation. Wiley-
VCH. p. 15. ISBN 978-3527313976.
• Vander; et al. (1998). Human Physiology. McGraw-Hill. p. 160. ISBN 978-0-07-
067065-5.