In biology, cell signaling is part of any communication process that governs basic activities of cells and coordinates multiple-cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis.

1. Cell Signaling
Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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2. Cell Signaling
In order to respond to changes in their immediate environment,
cells must be able to receive and process messages that originate
outside their borders which is known as cell signaling. Individual
cells often receive many signals simultaneously, and they then
integrate the information they receive into a unified action plan.
But cells aren't just targets. They also send out messages to other
cells both near and far.
What Kind of Signals Do Cells Receive?
Most cell signals are chemical in nature. For example, prokaryotic
organisms have sensors that detect nutrients and help them navigate
toward food sources. In multicellular organisms, growth factors,
hormones, neurotransmitters, and extracellular matrix components
are the major types of chemical signals that cells use. These
substances can exert their effects locally, or they might travel over
long distances.

3. Some cells also respond to mechanical stimuli. For example, sensory
cells in the skin respond to the pressure of touch, whereas similar
cells in the ear react to the movement of sound waves. In addition,
specialized cells in the human vascular system detect changes in
blood pressure .
In multi-cellular organisms there is a variety of signaling molecules
that are secreted or expressed on the cell surface of one cell and
bind to receptors expressed by other cells. These molecules
integrate and coordinate the functions of the cells that make up the
organism.
For instance, neurotransmitters are a class of short-range signaling
molecules that travel across the tiny spaces between adjacent
neurons or between neurons and muscle cells.

4. Endocrine (Hormonal) signaling:
The signaling molecules are
hormones secreted by
endocrine cells and carried
through the circulation
system to act on target cells
at distant body sites.
Paracrine signaling:
The signaling molecules
released by one cell act on
neighboring target cells
Autocrine signaling:
Cells respond to signaling
molecules that they
themselves produce (response
of the immune system to
foreign antigens,
and cancer cells).
Synaptic Signaling: involves in
nerve cells only

5. How Do Cells Recognize Signals?
Cells have proteins called receptors that bind to signaling molecules
and initiate a physiological response. Receptors are specific for
specific molecules. Dopamine receptors bind dopamine, insulin
receptors bind insulin, nerve growth factor receptors bind nerve
growth factor, and so on. In fact, there are hundreds of receptor
types found in cells, and different cell types have different set of
receptors. Receptors can also respond directly to light or pressure,
which makes cells sensitive to events in the atmosphere.
Receptors are generally transmembrane proteins, which bind to
signaling molecules outside the cell and subsequently transmit the
signal through a sequence of molecular switches to internal signaling
pathways.

6. Signal-Transduction
Once a receptor protein receives a signal, it undergoes a
conformational change, which in turn launches a series of
biochemical reactions within the cell. These intracellular signaling
pathways, also called signal transduction cascades, typically amplify
the message, producing multiple intracellular signals for each
receptor that is bound.
The trasnduction stage of cell signaling is usually a multistep
pathway. One benefit of such a pathway is signal amplification. If
one of the molecules in a pathway transmit the signal to multiple
molecules of the next component in the series, the result can be a
large number of activated molecules at the end of the pathway.
Therefore, a very small number of extracellular signal molecules
can produce a major cellular response.

8. Eukaryotic cells have six general types of signaling mechanisms:
1. Ligand Gated ion channels;
2. Receptor enzymes linked;
3. Membrane proteins that act through G proteins coupled receptor;
4. Nuclear proteins that bind steroids and act as transcription factors;
5. Membrane proteins that attract and activate soluble protein kinases; and
6. Adhesion receptors that carry information between the extracellular
matrix and the cytoskeleton.

10. Second Messengers
Activation of receptors can trigger the synthesis of small molecules called
second messengers, which initiate and coordinate intracellular signaling
pathways. These small molecules and ions are key components of signaling
pathways. The extra cellular signal molecule that binds to the membrane
receptor is a pathway's "first messenger". Because second messengers are
both small and water-soluble, they can readily spread throughout the cell by
diffusion. The most widely used second messengers are cyclic-AMP, IP3 and
calcium ions (Ca2+). A large variety of proteins are sensitive to the cytosolic
concentration of these second messengers.
Cyclic AMP (cAMP) Cyclic AMP is a component of many G-protein-signaling
pathways. The signal molecule - the "first messenger" - activates a G-
protein-linked receptor, which activates a specific G protein. In turn, the G
protein activates adenylyl cyclase, which catalyzes the conversion of ATP to
cAMP. GPCR also produces IP3 through activation of phospholipase-C.

11. Membrane Receptors for cell signaing:
Membrane receptors fall into three major classes:
•G-protein-coupled receptors (GPCR),
•Ion channel receptors, and
•Enzyme-linked receptors.
The names of these receptor classes refer to the mechanism by
which the receptors transform external signals into internal ones
— via protein action, ion channel opening, or enzyme activation,
respectively.
Because membrane receptors interact with both extracellular
signals and molecules within the cell, they permit signaling
molecules to affect cell function without actually entering the cell.
Not all receptors exist on the exterior of the cell. Some exist
deep inside the cell, or even in the nucleus.

12. GPCR:
A large family of plasma membrane receptors
with seven transmembrane segments act
through heterotrimeric G proteins. On ligand
binding, these receptors catalyze the
exchange of GTP for GDP bound to an
associated G protein, forcing dissociation of
the subunit of the G protein. This subunit
stimulates or inhibits the activity of a nearby
membrane-bound enzyme, changing the level
of its second messenger product.
Example: The binding of adrenaline to an
adrenergic receptor (GPCR Type) initiates a
cascade of reactions inside the cell. The signal
transduction cascade begins when adenylyl
cyclase, a membrane-bound enzyme, is
activated by G-protein molecules associated
with the adrenergic receptor. Adenylyl cyclase
creates multiple cyclic AMP molecules,
which activate protein kinase A (PKA). PKA
can enter the nucleus and affect transcription.
(GPCR)

13. How Do PKA Signals Affect Cell Function?
Protein kinases such as PKA catalyze the transfer of phosphate groups
from ATP molecules to protein molecules. Within proteins, the amino
acids serine, threonine, and tyrosine are especially common sites for
phosphorylation. These phosphorylation reactions control the activity of
many enzymes involved in intracellular signaling pathways. Specifically,
the addition of phosphate groups causes a conformational change in the
enzymes, which can either activate or inhibit the enzyme activity. Then,
when appropriate, protein phosphatases remove the phosphate groups
from the enzymes, thereby reversing the effect on enzymatic activity.
Phosphorylation allows for intricate control of protein function.
Phosphate groups can be added to multiple sites in a single protein, and a
single protein may in turn be the substrate for multiple kinases and
phosphatases.

14. Another pathway of GPCR action: IP3 functions as second
messenger
After activation of G-protein
by GPCR, it activates
Phospholipase C which
produces IP3 and DAG from
phosphatidyl inositol di-
phosphate (PIP2). IP3
functions as a second
messenger and open the Ca
channel of endoplasmic
reticulum. Calcium enters into
cytosol from ER and activates
various proteins for cellular
response.

15. Activation of protein kinase
C by hormone-activated
phospholipase C.
Two intracellular second
messengers are produced in
the hormone-sensitive
phosphatidylinositol system:
inositol 1,4,5-trisphosphate
(IP3) and
Diacylglycerol. Both contribute
to the activation of protein
kinase C.

16. Some Proteins Regulated by Ca2+ and Calmodulin
Adenylyl cyclase (brain)
Ca2+/calmodulin-dependent protein kinases (CaM kinases I to IV)
Ca2+-dependent Na channel (Paramecium)
Calcineurin (phosphoprotein phosphatase 2B)
cAMP phosphodiesterase
cGMP-gated Na, Ca2+ channels (rod and cone cells)
Glutamate decarboxylase
NAD kinase

17. Enzyme linked receptor:
Tyrosine-Kinase
Receptor
In the absence of specific
signal molecules, tyrosine-
kinase receptors exist as
single polypeptides in the
plasma membrane. When signal
molecules (such as a growth
factor, Insulin) attach to their
binding sites, two polypeptides
aggregate, forming a dimer
and activated. Each can then
initiate a signal-transduction
pathway leading to a specific
cellular response.

18. Ion-Channel Receptors:
Some membrane receptors of
chemical signals are Ligand-
gated ion channels. These
channels are protein pores in
the plasma membrane that open
or close in response to the
binding of a chemical signal,
allowing or blocking the flow of
specific ions, such as Na+ or Ca2+
into the cell. Often the change
in the concentration of a
particular ion inside the cell
directly affects cell function.

19. An acetylcholine receptor (green) forms a gated ion channel in
the plasma membrane. This receptor is a membrane protein with an
aqueous pore, meaning it allows soluble materials to travel across
the plasma membrane when open. When no external signal is
present, the pore is closed (center). When acetylcholine molecules
(blue) bind to the receptor, this triggers a conformational change
that opens the aqueous pore and allows ions (red) to flow into the
cell.
Example of Ion channel Receptor:

20. General mechanism by which
Thyroid and Steroid hormones
regulates gene expression:
1. Hormone (H), carried to the target
tissue on serum binding proteins,
diffuses across the plasma membrane
and binds to its specific receptor protein
(Rec) in the nucleus
2. Hormone binding changes the
conformation of Rec; it forms homo or
heterodimers with other hormone receptor
complexes and binds to specific regulatory
regions called hormone response
elements (HREs) in the DNA adjacent to
specific genes.
3. Binding regulates transcription of the
adjacent gene(s), increasing or decreasing
the rate of mRNA formation.
4. Altered levels of the hormone-regulated
gene product produce the cellular
response to the hormone.