Cell Communication

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 Overview: Cellular Messaging/Signaling
• Cell-to-cell communication is essential for both multicellular and
unicellular organisms

• Unicellular organisms
• To sense environment
• Is there enough food/light?
• Are there toxins in the vicinity?

• Cells in multicellular organisms

• To function cooperatively with neighboring and distant cells of the
organism
• Initiate protein synthesis only when enough glucose is present

The term cell signaling refers to the mechanisms by which cells communicate
with one another. If the cells are physically close to one another, a signaling
molecule on one cell may combine with a receptor on another cell. Most
commonly, cells communicate by sending chemical signals over some
distance.

The development and functioning of an organism require precise internal

communication as well as effective responses to the outside environment. In
plants and animals, hormones serve as important chemical signals between
various cells and organs.

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Evolution of Cell Signaling Receptor  factor

1 Exchange
• Biologists have discovered some of mating
a 
universal mechanisms of cellular factors
regulation
• Cells most often communicate with each Yeast cell,
a factor
Yeast cell,
other via chemical signals mating type a mating type 
• For example, the fight-or-flight
2 Mating
response is triggered by a signaling
molecule called epinephrine a 

• The yeast, Saccharomyces cerevisiae,

has two mating types, a and  3 New a/ cell
• different mating types locate each other
a/
via secreted factors

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 Four forms of intercellular signaling

Autocrine

Paracrine

Endocrine
Contact dependent

In a typical communication between cells, the signaling cell produces a

particular type of extracellular signal molecule that is detected by the target
cell. There are different forms of this process.

Autocrine
The cell secretes a hormone or chemical messenger that binds to autocrine
receptors on that same cell, leading to changes in the cell (self signaling).

Paracrine
The signal molecules diffuse locally through the extracellular fluid, remaining in
the neighborhood of the cell that secretes them. Thus, they act as local
mediators on nearby cells.

Contact –dependent
Direct contact between adjacent cell cytoplasm by gap junctions or
plasmodesmata.
Transport of ions and small molecules between cells
(e.g., between adjacent neurons)

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Endocrine
The signal is broad casted throughout the whole body by secreting it into an
animal’s bloodstream or a plant’s sap.
Extracellular signal molecules used in this way are called hormones, and, in
animals, the cells that produce hormones are called endocrine cells

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 The Three Stages of Cell Signaling
Reception, Transduction and Response

EXTRACELLULAR
EXTRACELLULAR CYTOPLASM
CYTOPLASM
FLUID
FLUID Plasma membrane
Plasma membrane

11 Reception
Reception 2 Transduction 3 Response

Receptor
Receptor
Activation
of cellular
response
Relay
Relay molecules
molecules in
in aa signal
signal transduction
transduction
pathway

Signaling
Signaling
molecule
molecule

When a signaling molecule binds to a receptor molecule on a target cell, signal

transduction occurs, leading to some response in the cell.
Cell signaling involves a series of processes.
First, a cell must send a signal. In chemical signaling, a cell must synthesize
and release signalling molecules.
Next, target cells must receive the information being signaled. This process is
called reception. In many cases, the signal molecule binds to a receptor on
the surface of the target cell.
Many signals do not actually enter the target cell. Signal transduction is the
process by which a cell converts an extracellular signal into an intracellular
signal that results in some response.
The signal is amplified as it is relayed through the cell, so the response is
much greater than would be possible if each signaling molecule acted alone

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 Reception: Signaling molecule
and Receptor Proteins
The binding between a signal molecule (ligand) and receptor is highly specific

Receptors are large proteins or glycoproteins that bind with signaling

molecules. A signaling molecule that binds to a specific receptor is called a
ligand.
Most ligands are hydrophilic molecules that bind to protein receptors on the
surface of target cells.

Some signaling molecules are small enough or sufficiently hydrophobic to

move through the plasma membrane and enter the cell. These signaling
molecules bind with intracellular receptors.

Reception occurs when a ligand binds to a specific receptor protein on the

surface of or inside a target cell. The signaling molecule activates the receptor.

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 Types of Receptors
Cell surface Intercellular

Most water-soluble signal molecules bind to specific sites on receptor proteins

that span the plasma membrane
There are three main types of membrane receptors
A. Ligand – gated Ion channel receptors
B. G protein-coupled receptors
C. Receptor tyrosine kinases

D. Is an intercellular receptor

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 Ligand-gated ion channel receptors

1 2 3

Gate
closed Ions Gate Gate closed
Signaling open
molecule
(ligand)

Plasma
Ligand-gated
membrane
ion channel receptor Cellular
response

Signaling molecule binds to channel allowing specific ions into cell

These ions produce cellular responses (Ca+2 one of the most important!)

A ligand-gated ion channel receptor acts as a gate when the receptor

changes shape
When a signal molecule binds as a ligand to the receptor, the gate allows
specific ions, such as Na+ or Ca2+, through a channel in the receptor

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 G-protein-coupled receptors (GPCRs)

• Energy source GTP turns on the G protein

• GDP turns it off

G protein-coupled receptors (GPCRs) are the largest family of cell-surface

receptors.

G protein–linked receptors (also called G protein– coupled receptors) are

transmembrane proteins that loop back and forth through the plasma
membrane seven times. The outer part of the receptor has a binding site for a
signaling molecule, and the part of the receptor that extends into the cytosol
has a binding site for a specific G protein.
The G stands for guanosine triphosphate (GTP), the compound to which the
G protein binds to when activated

When signalling molecule (ligand) binds to receptor, the ligand-receptor

complex associates with G protein. This causes GDP to be replaced with
GTP. One of the subunits of the G-protein separates from the receptor and
then turns on (or off) an enzyme

The G protein acts as an on/off switch: If GDP is bound to the G protein, the G
protein is inactive

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 Enzyme-coupled receptors

Examples
serine/threonine kinases
tyrosine kinase
cytokine receptors
guanylyl cyclase receptors

Enzyme-linked receptors function directly as enzymes or are linked to

enzymes. These receptors are transmembrane proteins with a binding site for
a signaling molecule outside the cell and an enzyme component inside the
cell. Some enzyme-linked receptors do not have an enzyme component but
have a binding site for an enzyme.

Several groups of enzyme-linked receptors have been identified. One group

consists of tyrosine kinases in which the tyrosine kinase enzyme is the domain
of the receptor that extends into the cytosol. (Recall that tyrosine is an amino
acid.) Tyrosine kinase phosphorylates specific tyrosine's in certain signalling
proteins inside the cell.

When signalling molecule (ligand) binds to receptors, receptors dimerize and

are enzymatically phosphorylated. Phosphate comes from ATP.

Many enzyme-coupled receptors have their own enzyme activity (intercellular

domain) however some rely on an enzyme that becomes associated with the
activated receptor).

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 Intracellular receptor: hormone signalling

Intracellular receptor proteins are found in the cytosol or nucleus of target cells
Small or hydrophobic chemical messengers can readily cross the
membrane and activate receptors
steroid and thyroid hormones of animals can act as a transcription factor,
turning on specific genes

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 Transduction; Signal Transduction Cascades

• Relay signals from receptors to target molecules in the cell

• Multistep pathways can amplify a signal
• provide more opportunities for coordination/regulation of
cellular response
• Involve Second messengers; small, nonprotein, water-soluble
molecules or ions that spread throughout a cell by diffusion
• Second messengers participate in pathways initiated by
GPCRs and RTKs
• Transmitted through a cell as a series of molecular events

Second messengers are ions or small molecules that relay signals inside the
cell. When receptors are activated, second messengers may be produced in
large quantities, thus amplifying the signal. Second messengers rapidly diffuse
through the cell (or membrane), relaying the signal. They are not enzymes, but
some regulate specific enzymes, such as protein kinases. Others bind to ion
channels, opening or closing them.

Some second messengers signal other molecules that pass the signal along
through a pathway of proteins and other molecules. The last molecule in the
sequence stimulates the final response. A chain of molecules in the cell that
relays a signal is called a signalling cascade.

Examples of second messengers

• cAMP, cGMP
• Lipids
• Calcium
• NO (nitrogen monoxide)

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 Molecular switches
Protein Kinase & Phosphatase

A B

Many molecules of the signalling transduction act as molecular switches,

activating or deactivating (inhibiting) other molecules.

These proteins can be activated—or in some cases inhibited—by the addition

or removal of a phosphate group.

A. In one class of switch protein, the phosphate is added covalently by a

protein kinase, which transfers the terminal phosphate group from ATP to
the signaling protein; the phosphate is then removed by a protein
phosphatase.
B. In the other class of switch protein, a GTP-binding protein is activated
when it exchanges its bound GDP for GTP (which, in a sense, adds a
phosphate to the protein); the protein then switches itself off by
hydrolyzing its bound GTP to GDP.

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 Signal Transduction
Phosphorylation cascade
A B

Proteins in the cytosol relay a signal from receptor

The receptor activates another protein, which activates another, and so on,
until the protein producing the response is activated.
At each step, the signal is transduced into a different form, usually a shape
change in a protein
One of the most common methods of regulating the signal is through
phosphorylation and dephosphorylation (Fig A). This phosphorylation and
dephosphorylation system acts as a molecular switch, turning activities on and
off or up or down, as required

Signaling molecules are typically present in very low concentration, yet their
effects on the cell are often profound. The binding of a single signalling
molecule can lead to changes in millions of molecules at the end of a signaling
cascade. This process of magnifying the strength of a signaling molecule is
called signal amplification (Fig B).

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 Response; vary by type and time – depend
on signal and reception

Every cell type displays a set of receptor proteins that enables it to respond to
a specific set of extracellular signal molecules produced by other cells. These
signal molecules work in combinations to regulate the behavior of the cell.
Cells may require multiple signals (blue arrows) to survive, additional signals
(red arrows) to grow and divide, and still other signals (green arrows) to
differentiate. If deprived of survival signals, most cells undergo a form of cell
suicide known as apoptosis

Certain types of cell responses—such as cell differentiation or increased cell

growth and division—involve changes in gene expression and the synthesis of
new proteins; they therefore occur relatively slowly.
Other responses—such as changes in cell movement, secretion, or
metabolism— need not involve changes in gene expression and therefore
occur more quickly (existing molecules within the cytosol activated or
released)

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 Response; same signal can cause deferent
response according to type of receptor

neurotransmitter

The same signal molecule can induce different responses in different

target cells.
Different cell types are configured to respond to the neurotransmitter
acetylcholine in different ways. Acetylcholine binds to similar receptor proteins
on heart pacemaker cells (A) and salivary gland cells (B), but it evokes
different responses in each cell type. Skeletal muscle cells (C) produce a
different type of receptor protein for the same signal. (D) For such a versatile
molecule, acetylcholine has a fairly simple chemical structure

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 Response; Signalling pathways
can be integrated
A B B

Signalling pathways can be integrated

A. One signalling molecules can activate several pathways

B. Different signalling molecules can activate the same pathways
C. Different pathways can be linked at different levels

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 EXAMPLE 1: Insulin signalling

Metabolic arm

Insulin signalling has two broad signalling pathways. One of them is fast acting
referred to as the metabolic arm – it alters the cells metabolism

The other is slow acting resulting in alteration of the transcriptome.

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 EXAMPLE 1: Insulin signalling in Muscle cells

When insulin binds to the insulin receptor (enzyme-linked receptor) the

receptors dimirise and a phosphprylation cascade is initiated.

The cascade results in:

1. Activation of glycogen synthetase by dephosphorylation leading to
glycogen synthesis.
2. Translocation and merging of GLUT4 (glucose carrier protein) to the
cellular membrane resulting in an increased uptake of glucose.

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 EXAMPLE 2: Anabolic Androgenic Steroids
Genomic action

Reproductive tissue Muscle tissue Bone tissue

PSA Protein synthesis Growth factor synthesis
Probasin Nitrogen retention Cell proliferation
Size and length erythropoiesis

Genomic actions are mediated by binding of testosterone or the respective

derivative to intracellular androgen receptors (iAR), resulting in dissociation
of heat-shock-protein 90 (HSP 90) and other chaperons from the receptors.
Subsequently, unprotected iAR dimerize and move to the nucleus, where they
are phosphorylated at several serine residues and continue to recruit several
co-activators like cAMP response element binding protein (CREB)-binding
protein (CBP),
p300/CBP-associated factor (p/CAF) and steroid receptor coactivator 1 (SRC-
1), etc.

In the following step, the receptor-coactivator-complexes bind to specific

androgen-response-elements (ARE) on the DNA, leading to chromatin
remodelling and recruitment of RNA-polymerase II. The enzyme transcribes
target DNA-regions into mRNA which, after translation, results in production of
different protein products. These are supposed to promote relevant changes in
different tissues.

Results of activation in productive tissue are increased levels of prostate

specific antigen (PSA) and production of probasin (an abundant protein that

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belongs to the lipocalin superfamily located in the nucleus of prostate and
seminal vesicle epithelial cells).
Muscle tissue is supposed to produce more protein while retaining nitrogen
and thereby increasing its size and strength.
Bone tissue answers stimulation by increased erythropoiesis, elevated cell
proliferation and increased synthesis of growth factors.

Parr and Muller-Scholl (2018) Pharmacology of doping agents—mechanisms

promoting muscle hypertrophy, AIMS Molecular Science, 5(2): 131–159.

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 EXAMPLE 2: Anabolic Androgenic Steroids
are Controlled Substances

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