Cell signaling allows cells to communicate and coordinate complex processes in the body. Chemical signals are sent between cells via signaling molecules that bind to receptors and trigger intracellular signaling cascades, resulting in cellular responses. There are several types of signaling molecules including paracrine and endocrine ligands. Receptors activate intracellular secondary messengers like cAMP, IP3, and calcium ions that propagate signals via pathways such as Wnt and Hedgehog. Recent advances include research on the SIRT1 gene and its role in chondrocyte differentiation as well as signaling pathways involved in diseases like polycystic kidney disease.

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CONTENTS:
1. Introduction
2. Stages
3. Types of Signaling Molecules
4. Receptors
5. Signaling Pathways
6. Types of Secondary Molecules
7. Recent Advancements
8. References

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1. INTRODUCTION:
Cell signaling refers to the vast networks of communication that
occur between and within each cell in our body.
Unlike the stable bricks that lay the foundation of our houses, cells
are dynamic and ever-active building blocks.
Cell signaling makes this possible. Together, cells are able to
coordinate everything from neonatal development to large,
cascading immune responses against bacteria or viruses.

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5. Think your cells are just simple building
blocks, unconscious and static as bricks in a
wall?
If so, think again!
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6. Cells can detect what's going on around them, and
they can respond in real time to cues from their
neighbors and environment.
At this very moment, your cells are sending and
receiving millions of messages in the form of
chemical signaling molecules!
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7. Cells typically communicate using chemical signals.
These chemical signals, which are proteins or other molecules
produced by a sending cell, are often secreted from the cell and
released into the extracellular space.
There, they can float – like messages in a bottle – over to
neighboring cells.
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8. 1. Sending cell:
This cell secretes a ligand.
2. Target cell:
This cell has a receptor that can bind the ligand. The ligand
binds to the receptor and triggers a signaling cascade
inside the cell, leading to a response.
3. Non target cell:
This cell does not have a receptor for the ligand (though it
may have other kinds of receptors). The cell does not
perceive the ligand and thus does not respond to it.
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9. Not all cells can “hear” a particular chemical message. In
order to detect a signal (that is, to be a target cell), a
neighbor cell must have the right receptor for that signal.
When a signaling molecule binds to its receptor, it alters
the shape or activity of the receptor, triggering a change
inside of the cell.
Signaling molecules are often called ligands, a general
term for molecules that bind specifically to other molecules
(such as receptors).
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10. The message carried by a ligand is often relayed through a chain of
chemical messengers inside the cell.
Ultimately, it leads to a change in the cell, such as alteration in the
activity of a gene or even the induction of a whole process, such as
cell division.
Thus, the original intercellular (between-cells) signal is converted
into an intracellular (within-cell) signal that triggers a response.
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2. STAGES:
Reception, whereby the signal molecule binds the receptor
Transduction, which is where the chemical signal results in
a series of enzyme activations
Finally, the response, which is the resulting cellular
responses.

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TRIGGERING
SIGNAL
PRODUCING CELL
(biosynthesis, storage,
secretion)
HORMONE
TARGET
CELL
DEGRADATION
SIGNAL
FEEDBACK
TRIGGER SIGNAL
SIGNAL FORMATION
TRANSPORT
PROCESSING
REGULATION

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3. TYPES OF SIGNALING MOLECULES:
Intracrine ligands are produced by the target cell itself and bind to a
receptor within.
Autocrine ligands are finely distinct in that although they are also
made by the target cell, they are first secreted and then later bind to
the cell as well as neighboring cells (ex. Immune cells).
Juxtacrine ligands target adjacent cells (often called “contact-
dependent” signaling).
Paracrine ligands target cells in the vicinity of the original emitting
cell (ex. Neurotransmitters like Acetylcholine).
Endocrine cells produce hormones that have the important task of
targeting distant cells and often travel through our circulatory
system.

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4. RECEPTORS:
1. Receptors for cell signaling mainly are of two types namely cell surface
receptors and intracellular or internal receptors.
2. Those signaling molecules which are capable of diffusing into cytosol of the
cell can interact with internal receptors and execute signaling process.
3. Steroid molecules and Nitric oxide are examples of signaling molecules
which can bind to internal receptors.
4. They participate in intracellular signaling process.

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5. SIGNALING PATHWAYS:
Wnt PATHWAY:
1. The name Wnt was coined as a combination of Wg (wingless)
and Int and can be pronounced as 'wint'.
2. The wingless gene had originally been identified as a segment
polarity gene in Drosophila melanogaster that functions during
embryogenesis and also during adult limb formation during
metamorphosis.
3. The INT genes were originally identified as vertebrate genes
near several integration sites of mouse mammary tumor virus
(MMTV).

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HEDGEHOG PATHWAY:
1. The hedgehog signaling pathway is one of the key regulators of
animal development conserved from flies to humans.
2. The pathway takes its name from its polypeptide ligand, an
intercellular signaling molecule called Hedgehog (Hh) found in
fruit flies of the genus Drosophila.
3. Hh is one of Drosophila's segment polarity gene products,
involved in establishing the basis of the fly body plan. The
appearance of the stubby and "hairy" larvae inspired the name
'hedgehog' when the gene mutated.

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CELL SURFACE RECEPTORS:
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 ligand-binding domain.
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.

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TYPES OF CELL SURFACE RECEPTORS:
1. G-protein coupled receptors
2. Receptor tyrosine kinase receptors
3. Cytokine receptors and Non-tyrosine kinase receptors
4. Integrin receptors
5. Toll-like receptors
6. Ligand gated ion-channels receptors
7. Receptors with other enzymatic activities

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INTEGRIN RECEPTORS:
Integrins are produced by a wide variety of cell types, and play a role in the
attachment of a cell to the extracellular matrix (ECM) and to other cells, and in the
signal transduction of signals received from extracellular matrix components such
as fibronectin, collagen, and laminin.
Ligand-binding to the extracellular domain of integrins induces a conformational
change within the protein and a clustering of the protein at the cell surface, in
order to initiate signal transduction.

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TOLL-LIKE RECEPTORS:
1. Toll-like receptors (TLRs) are a class of single membrane-spanning non-
catalytic receptors that recognize structurally conserved molecules derived
from microbes once they have breached physical barriers such as the skin or
intestinal tract mucosa, and activate immune cell responses.
2. They play a key role in the innate immune system.
3. They receive their name from their similarity to the protein coded by the Toll
gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard.

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These intracellular messengers have some properties in common:
They can be synthesized/released and broken down again in specific
reactions by enzymes or ion channels.
Some (like Ca2+) can be stored in special organelles and quickly
released when needed.
Their production/release and destruction can be localized, enabling
the cell to limit space and time of signal activity.

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6.TYPES OF SECONDARY MOLECULES:
There are three basic types of secondary messenger molecules:
Hydrophobic molecules: water-insoluble molecules, like
diacylglycerol, and phosphatidylinositols, which are membrane-
associated and diffuse from the plasma membrane into the juxta
membrane space where they can reach and regulate membrane-
associated effector proteins
Hydrophilic molecules: water-soluble molecules, like cAMP, cGMP,
IP3, and Ca2+, that are located within the cytosol
Gases: nitric oxide (NO) and carbon monoxide (CO), which can
diffuse both through cytosol and across cellular membranes.

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Different terminologies used to differentiate intracellular
messengers or molecules namely:
Primary effector, Secondary messenger and Secondary effector.
Primary effectors include Adenylate cyclase, Guanylate cyclase,
Phospholipase-C, Phospholipase-A and Receptor tyrosine kinase.
Secondary messenger include cAMP, cGMP, IP3 and
DAG. Secondary effector include Protein kinase-A, Protein kinase-
G, Protein kinase-C and Calcium ions.

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Second
Messenger
Hormones Function
Cyclic AMP Epinephrine and nor-
epinephrine, glucagon,
luteinizing hormone,
follicle stimulating
hormone
Activates Protein kinase-A
Cyclic GMP Atrial naturetic hormone,
nitric oxide
Activates Protein kinase-G and
opens cation channels in rod cells
DAG Epinephrine and
norepinephrine,
angiotensin II
Activates Protein kinase-C
IP3 Epinephrine and
norepinephrine,
angiotensin II,
antidiuretic hormone
Opens calcium channels in ER

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NITRIC OXIDE (NO) AS SECOND MESSENGER:
1. The gas nitric oxide is a free radical that diffuses through the
plasma membrane and affects nearby cells.
2. NO is made from arginine and oxygen by the enzyme NO
synthase, with citrulline as a by-product.
3. NO works mainly through activation of its target receptor, the
enzyme soluble guanylate cyclase, which, when activated,
produces the second messenger cyclic-guanosine monophosphate
(cGMP).

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7. RECENT ADVANCEMENTS:
1. SIRT1 is a highly conserved type III acetyltransferase gene
located on chromosome 10 in mammals that belong to
the Sirtuins family. In order to explore the effects of the SIRT1
gene in the ATDC5 cell line, an RNAi SIRT1 target
sequence was designed and synthesized, aimed to knockdown
the expression of SIRT1 in ATDC5 by a lentivirus.
2. Polychlorinated biphenyl-mediated steatohepatitis has been
shown to be due in part to inhibition of epidermal growth
factor receptor (EGFR) signalling.

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3. Autosomal dominant polycystic kidney disease (ADPKD) is
caused by mutations in genes encoding the polycystin (PC) 1
and 2 proteins. The goal of this study was to determine the role
of calcium in regulating cyst growth.
4. Excessive vascular smooth muscle cell (SMC) proliferation,
migration and extracellular matrix (ECM) synthesis are key
events in the development of intimal hyperplasia, a
pathophysiological response to acute or chronic sources of
vascular damage that can lead to occlusive narrowing of the
vessel lumen.

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8. REFERENCES:
1. Cullen, P.J.; Lockyer, P.J.; (2002) “Integration of Calcium
and Ras signalling”; Cell Biol; pp. 3:339–348.
2. Cooper, D.M.; (2003) “Regulation and Organization of
Adenylyl Cyclases and Camp”. Biochem. J; pp. 375:517–
529.
3. Whorton, M.R; Sunahara, R.K; (2003) “Adenylyl cyclases:
In Handbook of Cell Signaling”; Vol. 2 (Bradshaw, R.A. and
Dennis, E.A); Academic Press; San Diego; pp. 419–426

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