1.

Introduction

A typical cell in a multicellular

organism is exposed to hundreds of
different signal molecules in its
environment. Each cell type displays
a set of receptors that enables it to
respond to a corresponding set of
signal molecules produced by other
cells. These signal molecules work in
various combinations to regulate the
behavior of the cell (Figure 1). Cell
communication modes resembling our
own communication system. Cells
communicate by chemicals and
chemical modifications of receptors, Figure 1. An animal cell's dependence on
and intracellular signaling molecules multiple extracellular signal molecules
that are translated into a change of Figure 2. A intracellular signaling pathway
cell fate/cellular. activated by an extracellular signal molecule

Communication between cells in multicellular organisms is mediated mainly by extracellular signal

molecules. Some of these operate over long distances signaling to cells far away; others signal only to
immediate neighbors. Reception of the signals depends on receptor proteins, which bind the signal molecule.
The binding activates the receptor, which in turn activates one or more intracellular signal pathways. These
systems depend on intracellular signaling proteins, which process the signal inside the cell. The targets that
lie at the end of the pathway are generally called effector proteins. These effectors can be transcription
regulators, ion channels, components of a metabolic pathway or parts of the cytoskeleton (Figure 2).

Forms of intercellular signaling

Many of the same types of signaling molecules are used in paracrine, synaptic and endocrine signaling. The
crucial differences lie in the speed and selectivity with which the signals are delivered to their targets (Fig 3).

Contact-dependent signaling: requires cells to be in direct membrane-membrane contact. It's

especially important during development and in immune responses.
Paracrine signaling: depends on local mediator that are released
into the extracellular space and act on cells in the local
environment. These mediators act with a low average life time.
Usually the signaling cell and the target cell are different, but
certain kind of cells (like cancer cells) can produce signals that
they themselves respond to (autocrine signaling).
Synaptic signaling: is perform by neurons that transmit signals
electrically along their axons and release neurotransmitters at
chemical synapses, which are often located far away from the
neural cell body. Fast and precise. High local concentration.
Endocrine signaling: depends on endocrine cells, which secrete
hormones into the bloodstream for distribution throughout the
body. The hormones act on target cells far away from the
signaling cell (high average life time). Slow signaling, very low
concentration.
Figure 3. Four forms of intercellular signaling
Receptors

The receptor binds the signal molecule and then initiates a response in the target
cell. The binding site of the receptor has a complex structure that is shaped to
recognize the signal molecule with high specificity. Many signal molecules act at
very low concentrations and their receptors usually bind them with high affinity.

In most cases, receptors are transmembrane proteins on the target-cell surface (cell-
surface receptors) and they bind an extracellular signal molecule (ligand). These
molecules are hydrophilic and are therefore unable to cross the target cell's
membrane directly and bind to cell-surface receptors.
In other cases, the receptor proteins are inside the target cell and the signal molecule
has to enter the cell to bind to them (intracellular receptors). This requires a signal
molecule sufficiently small and hydrophobic to diffuse across the target cell's
membrane and bind to receptor proteins either in the cytosol or in the nucleus. As
these molecules are hydrophobic, they are transported in the bloodstream and other
extracellular fluids bound to carrier proteins (Figure 4). Figure 4. The binding of extracellular
signal molecules to either cell-surface
or intracellular receptors
The same signal can lead to multiple responses

A signal molecule often has different effects on different types of target

cells. The neurotransmitter acetylcholine (Figure 5), decreases the rate of
action potential firing in heart pacemaker cells and stimulates the
production of saliva by salivary gland cells, even though the receptors
are the same (GPCR). In skeletal muscle, Ach causes the cells to contract
by binding to a different receptor protein.

Also, cells react differently to different strength of the

same signal. The fate of some cells depends on their
position in Morphogen gradients (Figure 5).

The different effects result from differences in the

intracellular signaling proteins, effector proteins and Figure 5. Various responses induced by
genes that are activated. acetylcholine and effect of the morphogen gradients

Intracellular signaling pathways

Some intracellular signaling molecules are small chemicals,

which are often called second messengers, generated in large
amounts in response to receptor activation and diffuse away
from their source. cAMP and Ca+2 are water-soluble (cytosol)
and diacylglycerol (DAG) is lipid-soluble (membrane).

Most intracellular signaling molecules are proteins, which act as

molecular switches. The largest class of molecular switches
consists of proteins that are activated or inactivated by
phosphorylation (Figure 6A). For this proteins, the switch is
thrown in one direction by a protein kinase and in the other
direction by a protein phophatase. There are two main types of
protein kinase: Ser/Thr kinases (hydroxyl groups) and tyrosine
kinases. Figure 6. Two types of intracellular signaling proteins that act
as molecular switches
The other important class of molecular switches consists of GTP-binding proteins (Figure 6B). These
proteins switch between an on state when GTP is bound and off state when GDP is bound. There are two
mayor types of GTP-binding proteins: trimeric GTP-binding proteins (G proteins) and small monomeric
GTPases. Specific regulatory proteins control both types of GTP-binding proteins. GTPase-activating
proteins (GAP) drive proteins into an off state and guanine nucleotide exchange factors (GEFs) activate
them.

Mayor classes of cell-surface receptor proteins

Receptor act as signal transducers by converting an extracellular event into intracellular signals that alter the
behavior of the target cell. Most cell-surface receptor proteins belong to one of three classes (Figure 6):

Ion-channel-coupled receptors: also known as ionotropic

receptors, are involved in rapid synaptic signalling between nerve
cells and other electrically excitable target cells (nerve, muscle...).
This signaling is mediated by a small number of neurotransmitters
that transiently open or close an ion channel and changing the ion
permeability of the plasma membrane and the excitability of the
postsynaptic target cell. Most belong to a family of multipass
transmembrane proteins.
G-protein-coupled receptors (GPCR): a trimeric G-protein
mediates the interaction between the activated receptor and its
target protein. Its activation can change the concentration of
signaling molecules (if the target protein is an enzyme) or it can
change the ion permeability of the membrane.
Enzyme-coupled receptors: can be either function as enzymes or
be associated directly with enzymes that they activate. They are
usually single-pass transmembrane proteins that have their ligand-
binding site outside the cell and their catalytic or enzyme-binding
domain inside.
Figure 6. Three classes of cell-surface receptors