This document discusses cell signaling systems. It describes how signal reception and transduction are key events in cell communication. The main components of a signaling system are ligands, which bind to receptors and provide signals to cells, and receptors, which are proteins that receive ligands and activate intracellular signaling pathways. When ligands bind to receptors, they trigger cascades of intracellular signaling proteins that alter target proteins and change cell behavior. Different cell types possess different receptors and signaling pathways, allowing cells to have specialized responses to signals.

1. Dept. of Natural
Sciences
University of St. La
Salle
Bacolod City

2. CELL SIGNALING SYSTEM
 Cell communication begins when a receptor
protein on the target cell receives an
incoming extracellular signal and converts it
to the intracellular signals that direct cell
behavior.
 Signal reception
and signal
transduction
are the events
referred to in
cell signaling.

3. COMPONENTS OF A SIGNALING SYSTEM
1. LIGAND - a molecule that binds to a specific site
on another molecule, usually a protein receptor;
provides a signal or an external message to the
cell; also known as primary messenger
 Peptides / Proteins- growth Factors
 Amino acid derivatives - epinephrine, histamine
 Other small biomolecules - ATP
 Steroids, prostaglandins
 Gases - Nitric Oxide (NO)
 Photons
 Damaged DNA
 Odorants, tastants
2. RECEPTOR- typically an extracellular ligand-
binding molecule; a few are cytoplasmic forms

4. When a ligand binds
to a receptor
protein, this activates
a signal transduction
pathway that is
mediated by a series
of intracellular
signaling proteins.
These interact with
target
proteins, altering
them to change cell
behavior. The
repertoire of changes
a cell can show
depends on which
receptors it
possess, how these
are coupled to signal
transduction
pathways, and how
these are coupled to

5.  A ligand binds its receptor through a  In situations
number of specific weak non-covalent where even low
bonds by fitting into a specific binding concentrations
site or "pocket". of a ligand will
result in binding
of most of the
cognate
receptors, the
receptor affinity
is considered to
be high (Ka).
 Low receptor
affinity occurs
when a high
concentration of
the ligand is
required for
most receptors
to be occupied.

6.  With prolonged exposure to a ligand (and occupation
of the receptor) cells often become desensitized.
 Desensitization of the cell to a ligand depends upon
receptor down-regulation by either:
o removal of the receptor from the cell surface
(receptor-mediated endocytosis) or,
o alterations to the receptor that lower the affinity
for ligand or that render it unable to initiate the
changes in cellular function (such as
phosphorylation).
 Desensitization may lead to tolerance, a phenomenon
that results in the loss of medicinal effectiveness of
some medicines that are over prescribed.
 Receptor binding activates a "preprogrammed"
sequence of signal transduction events that may
require immediate responses; others maybe slow.

7. Changes in cell May
movement, involve
secretion, or genes
metabolism (e.g.,
(i.e., rapid increased
phosphorylation cell growth
of target and
proteins) division

8. Every cell type displays Cell responses to signals may vary
a set of receptor
proteins that enables it
to respond to a specific
set of 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
divide, and still other
signals (green arrows) to
differentiate. If deprived
of survival signals, most
cells undergo a form of
cell suicide known as
programmed cell
death, or apoptosis.

9. Cells use different strategies for sending signals
A.Hormones produced in endocrine glands are secreted into
the bloodstream and are often distributed widely
throughout the body.
B.Paracrine signals are released by cells into the
extracellular medium in their neighborhood and act locally.

10. C. Neuronal signals or neurotransmitters are transmitted
along axons to remote target cells.
D. Cells that maintain an intimate membrane-to-membrane
interface can engage in contact dependent ( juxtacrine)
signaling.
 Many of the same types of signal molecules are used for
endocrine, paracrine, and neuronal signaling.
 The crucial differences lie in the speed and selectivity with
which the signals are delivered to their targets.

11. Contact-dependent signaling controls nerve-cell production.
The signals that control the process of nerve cell specialization
from an embryonic epithelial sheet are transmitted via direct cell–
cell contacts: each future neuron delivers an inhibitory signal to
the cells next to it, deterring them from specializing as neurons
too. Both the signal molecule (Delta)
and the receptor molecule (Notch) are
transmembrane proteins. In mutants
where the mechanism
fails, some cell
types (such as
neurons)
are produced
in great
excess
at the
expense
of others.

12. CELL SIGNALING CASCADES
 They transform, or transduce, the signal
into a molecular form suitable for passing
the signal along or stimulating a response.
 They relay the signal from the point in the
cell at which it is received to the point at
which the response is produced.
 In many cases, signaling cascades also
amplify the signal received, making it
stronger, so that a few extracellular signal
molecules are enough to evoke a large
intracellular response.
 The signaling cascades can also distribute
the signal so as to influence several
processes in parallel: at any step in the
pathway, the signal can diverge and be
relayed to a number of different
intracellular targets, creating branches in
the information flow diagram and evoking a
complex response.
 Each step in this signaling cascade is open
to modulation by other factors, including
other external signals, so that the effects of
http://highered.mcgraw-
the signal can be tailored to the conditions
hill.com/sites/0072437316/student_view0
prevailing inside or outside the cell.
/chapter7/animations.html#

13. There are different ways in which signals maybe integrated:

14. INTRACELLULAR RECEPTORS

15. Intracellular signaling proteins act as molecular switches.
Intracellular signaling proteins can be activated by the addition of a
phosphate group and inactivated by the removal of the phosphate. In some
cases, the phosphate is added covalently to the protein by a protein kinase
that transfers the terminal phosphate group from ATP to the signaling protein;
the phosphate is then removed by a protein phosphatase (A). In other cases, a
GTP-binding signaling protein is induced to exchange its bound GDP for GTP;
hydrolysis of the bound GTP to GDP then switches the protein off (B).

16. Some
intracellular
signaling proteins
serve to integrate
incoming
signals.
Signals A and B may activate different cascades of protein
phosphorylations, each of which leads to the phosphorylation of protein
Y but at different sites on the protein (A). Protein Y is activated only when
both of these sites are phosphorylated, and therefore it is active only
when signals A and B are simultaneously present. Alternatively, signals A
and B could lead to the phosphorylation of two proteins, X and Z, which
then bind to each other to create the active protein XZ (B).

19. NEUROTRANSMITTERS
Acetylcholine can induce different responses in different target
cells. Different cell types are configured to respond to
acetylcholine in different ways. Acetylcholine binds to similar
receptor proteins on heart muscle 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. The different receptor types generate
different intracellular signals, thus enabling the different types of
muscle cells to react differently to acetylcholine. (D) For such a
versatile molecule, acetylcholine has a fairly simple structure.

20. HORMONES
 Chemical signals known as hormones are
secreted by one tissue to regulate another
tissue, often over a distance.
 Hormones are often transmitted by the
circulatory system.
 Hormones control many physiological functions
including growth and development, rates of
physiological processes, concentrations of
sugars and minerals, and responses to stress.
 Hormones can be amino acid derivatives
(epinephrine), peptides (antidiuretic
hormone, vasopressin), proteins (insulin), or
lipid-like hormones including steroids
(testosterone)

21. Hormonal signals can be classified by the distance
that they travel to reach their target cells.
1.An endocrine hormone travels through the
circulatory system and a paracrine hormone acts
only upon near by cells. A paracrine hormone is
roughly equal to a growth factor.
2.Endocrine tissues secrete directly into the blood-
stream and exocrine tissues into ducts for transport
of the secretions to other parts of the body.
o The pancreas has both endocrine (insulin and
glucagon) and paracrine (digestive enzymes)
functions.
o Once in the circulatory system, the endocrine
hormones will eventually reach their target
tissue(s) such as heart and liver (epinephrine) or
liver and skeletal muscles (insulin).

22. The steroid hormone
cortisol acts by activating
a gene regulatory protein.
Cortisol diffuses directly
across the plasma
membrane and binds to
its receptor protein, which is
located in the cytosol. The
hormone–receptor complex
is then transported into the
nucleus via the nuclear
pores. Cortisol binding
activates the receptor
protein, which is then able to
bind to specific regulatory
sequences in the DNA and
activate gene transcription.
The receptors for cortisol
and some other steroid
hormones are located in the
cytosol; those for the other
signal molecules of this
family are already bound to
DNA in the nucleus.

23. GROWTH FACTORS
 Growth factors act as primary messengers.
 In addition to nutrients, cell often need growth factors to
grow including: Platelet-derived growth factor (PDGF),
Insulin, insulin-like growth factor 1 (IGF-1), fibroblast
growth factor (FGF), epidermal growth factor (EGF),
nerve growth factor (NGF)
 These RTK ligands function in much more than growth
and cell division.

24. Disruption of growth factor signaling
through RTKs can have dramatic
effects on embryonic development.
The fibroblast growth factors (FGFs)
and fibroblast growth factor
receptors (FGFRs) function in both
embryonic and adult signaling.
FGFRs are important in the development of mesoderm, the embryonic tissue
that eventually becomes muscle, cartilage, bone and blood cells. A mutant
receptor that, due to dimerization with normal versions of FGFR, has a dominant
inhibitory effect upon the normal activity is a dominant negative mutation.

25. A dominant negative
mutant version of FGFR
mRNA injected into frog
eggs cause the failure of
mesodermal tissue to
develop and produces
tadpoles with heads but
no bodies. In
humans, defects in
FGFRs lead to
thanatophoric dysplasia
severe bone
abnormalities (fatal in
infancy) and
achondroplasia
(dwarfism).

26. CALCIUM AS A SIGNAL
 Ca+2 ions act to
regulate many
cellular functions.
 The release of Ca+2
ions is a key event
in many signaling
processes.
 Intracellular
concentrations can
be followed by
injection of Ca+2
indicator
fluorescent
dyes, presence of
ligand or increase
in IP3 and
monitoring the
increase in  Ca+2 levels in the cytoplasm is normally kept low (10-4) by Ca+2
fluorescence. pumps in the plasma membrane (out of the cell) and by sodium-
 The Ca+2 ionophore calcium exchangers: a) out of the cell, b) into ER lumen and c)
releases Ca+2 from into the mitochondrion.
the intracellular  Ca+2 stores can be released from the ER by the IP3 receptor
stores that mimics channel and ryanodine receptor channel which opens in the
effect of IP3 presence of Ca+2 itself (Ca+2 -induced Ca+2 release).
activation.

27. Although other proteins bind Ca+2 to control
When Ca+2 ions are activity, most often binding to the protein
present, two bind calmodulin, forming a Ca+2-calmodulin
each globular end complex is an intermediate step.
(4 in total); the
helical arm region
then changes
conformation (the
active complex) and
then wraps around
the calmodulin-
binding site of
target protein
kinases and
phosphatases
which may vary
depending upon the
target cell (different
cells have different
responses).

28. Fertilization of animal eggs reveals an important
example of calcium-mediated signal transduction
after a receptor-ligand interaction. Initially the
sperm binds the egg’s surface at the membrane and
within 30 seconds, a wave of calcium release
spreads from the site of sperm contact.
Two main events in fertilization rely on calcium release:
 Calcium stimulates the fusion of the cortical granules with the egg’s
plasma membrane to alter the coat surrounding the egg to help prevent
the binding of another sperm cell to the egg (slow block to polyspermy).
 Calcium initiates egg activation, the resumption of metabolic processes.

29. The conversion of glucose
into pyruvate is thus
accelerated, resulting in an
increase in the
concentration of ATP in the
cytosol (2). The binding of
ATP to ATP-sensitive K
channels closes these
channels (3), thus reducing
the efflux of K ions from the
cell. The resulting small
depolarization of the
plasma membrane (4)
triggers the opening of
voltage-sensitive Ca+2
channels (5). The influx of
Ca+2 ions raises the
Secretion of insulin from pancreatic cells in cytosolic Ca+2
concentration, triggering
response to a rise in blood glucose. The entry of
the fusion of insulin-
glucose into cells is mediated by the GLUT2
containing secretory
glucose transporter (1). A rise in extracellular
vesicles with the plasma
glucose from 5 mM, (fasting state), causes a
membrane and the
proportionate increase in the rate of glucose entry.
secretion of insulin (6).

30. NITRIC OXIDE AS A SIGNAL
 Nitric oxide (NO) is a toxic, short-lived gas
molecule and has been found to be a
signaling molecule in the cardiovascular
system.
 The binding of acetylcholine causes the
release of NO in vascular endothelial cells.
 NO may couple the G protein-linked receptor
stimulation in endothelial cells to relaxation
of smooth muscle cells in blood vessels.
 Note that NO gas is highly toxic when inhaled
and should not be confused with nitrous
oxide (N2O), also known as laughing gas.

31. Regulation of contractility of arterial smooth muscle by nitric oxide (NO) and cGMP.
Upon activation by acetylcholine, NO diffuses from the endothelium and activates an
intracellular NO receptor with guanylyl cyclase activity in nearby smooth muscle cells.
The resulting rise in cGMP leads to activation of protein kinase G (PKG), relaxation of the
muscle, and thus vasodilation. The cell-surface receptor for atrial natriuretic factor (ANF)
also has intrinsic guanylyl cyclase activity. Stimulation of this receptor on smooth muscle
cells also leads to increased cGMP and subsequent muscle relaxation.

32. Odorants (scent
chemicals) activate Gs
and adenylate cyclase
in scent-sensitive
nerve cells. cAMP then
opens a non-selective
cation channel in the
plasma membrane.

34. CELL SIGNALING AND APOPTOSIS
 Cells regulate programmed cell death (PCD) or apoptosis which
is a very ordered mechanism to prune away unneeded
structures, control the number of cells in particular tissues, and
sculpt complex organs.
 It is an important part of normal development (removal of
webbing of fingers and toes in embryos, extra neurons in infants
and old blood cells in adults).
 There is some evidence that activation of the apoptosis pathway
in adult neurons is responsible for Alzheimer’s disease and CV
stroke.
 The cell death program involves the activation specific
proteases known as caspases and procaspases.
 The Fas ligand on the surface of lymphocytes bind the Fas
receptors on the infected cell’s surface. This results in the
clustering of Fas, the attachment of adaptor proteins and
assembly of the procaspases at this site. The procaspases
activate each other to start a cascade of events that ends in
apoptosis.

39. http://www.sinauer.com/cooper/4e/animations1501.html
http://www.sinauer.com/cooper/4e/animations1502.html
http://www.sinauer.com/cooper/4e/animations1503.html
http://www.wiley.com/college/boyer/0470003790/animations/signal_
transduction/signal_transduction.htm
http://bcs.whfreeman.com/thelifewire/content/chp15/15020.html
http://www.whfreeman.com/kuby/content/anm/kb02an01.htm
http://www.bio.davidson.edu/courses/Immunology/Flash/MAPK.html
http://www.whfreeman.com/kuby/content/anm/kb02an01.htm