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Cellular Signalling

LECTURE SERIES
Session Chapter and Description Reference
1
Introduction to cellular signalling
Campbell et al. 2010. Biology.
Chap 11.

Lodish et al 1995. Molecular Cell
Biology 3rd ed. Chap 20-21.
2
Nerve and Immune cell signalling
3
Introduction to receptor and ligand
4
Receptors for Tyrosine kinase

5
G-protein signalling

6
Cytokine signalling
Phelps, et al. 2008. Cytokines and
the brain. Chap 1.
7
MAP kinase

8
Growth signalling: Growth hormone and JAK/STATS

9
Apoptosis

10
Inflammatory signalling

11
Pain and receptors

12
Phosphatases, PTEN and cancer

Case studies
Week 3: Nerve and immune cell signalling
Week 7: Non-inflammatory, Pro-inflammatory, and Anti-inflammatory cytokine signalling
Week 10: Apoptosis or necrosis?

Introduction to
Cell communication
LECTURE 1: CELLULAR SIGNALLING
What is cell signalling?
How do cells receive and respond to signals from their surroundings.
Prokaryotes and unicellular eukaryotes are largely independent and
autonomous.
In multicellular organisms there is a variety of signalling 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.
Cells
The plasma membrane
is fluid mosaics of lipids and proteins, it consists of double
layer of phospholipids and other lipids with attached proteins.
controls traffic into and out of the cell it surrounds
is selectively permeable, it allows sufficient passage of
oxygen a nutrients and elimination of wastes
Phospholipids are
amphipatic molecules
Lipids and proteins
Proteins are embeded or
attached to surface.
The fluidity
Is due to the presence of
unsaturated
hydrocarbons, which
increase fluidity and
cholesterol (animal
cells), which reduces
fluidity; helps stabilize
the membrane
Proteins in
membrane
determine many of the
membranes specific
functions
Integral proteins
transmembrane proteins
Peripheral proteins are
not embeded in the lipid
bilayer
Transport
Active transport is the
pumping of solutes against
concentration gradients
uphill
It is the major mechanism of
ability of cell to maintain
internal concentrations of
small molecules that differ
from concentrations in
environment.
Modes of cell-cell signaling
Direct cell-cell or cell-matrix (integrins and cadherins)
Indirect: Secreted molecules.
Endocrine 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 (neurotransmitters).
Autocrine signaling. Cells respond to signaling molecules that they themselves
produce (response of the immune system to foreign antigens,and cancer cells).


Cell communication function of proteins
Direct contact between membranes by cell-surface molecules
= cell junctions = intracellular joining
= cell-cell recognition (glycolipids and glycoproteins)

Intracellular junctions (joining)
Cell walls of plant cells perforated with channels called plasmodesma.
In animals are intracellular junctions.

Tight junction
Desmosomes
Gap junctions

Adhere, interact
and communicate
Cell-cell recognition is done
also by carbohydrates (linked to
proteins and lipids), which
helps to sort cell into tissues and
organs in embryo and
helps to recognize and reject the
foreign cells in the immune system

Carbohydrates are usually
short branched
oligosaccharides.
Attachment with ECM
Plant cells (some Protists, prokaryotes, fungi) encased
by cell walls
Animal extracellular matrix ECM with
glycoproteins :
Collagen fibers are embedded in network
of proteoglycans.
Fibronectins bind to receptor
protein called integrins in plasma
membrane. Integrins bind to
microfilaments (cytoskeletal pr.)
on cytoplasmatic side.
Signal
transduction
pathways
Cell communication: Local and long-
distance signaling
Cell communication and signal
transduction function of protein
Cell responds to external signals.
A signaling molecule (ligand/first messenger) binds to a receptor
protein in membrane and causes a change of his shape (enzyme).
On internal side is the signal transformed in the cascade of
molecular interactions with origin of second messengers. In
nucleus signal leads to regulation of transcription or other
cytoplasmatic activities.
Cell signaling
1. Reception: target cell detects a signaling molecule coming
from outside
2. Transduction: change of the receptor protein initiating
process of cellular response (enzymatic)
3. Response: cellular activity: catalysis, rearrangement of the
cytoskeleton, activation of genes
Reception
Signaling molecule + Receptor
Receptor or protein associated with get activated and it is able to transfer the
signal inside the cell.

G protein coupled receptors / inhibitory or activity
Receptor tyrosine kinases have enzymatic activity and catalyze transfer of
phosphate groups
Ion channel receptors with gate open or close
Intracellular
receptors for steroid
and thyroid hormones,
nitric oxide
Transduction
Multistep pathway (cascade) of activation of proteins by addition or
removal of phosphate groups or it starts by the origin of small
molecules or ions that act as seconder messengers.

Phosphorylation and dephosphorylation of proteins acts as a molecular
switch.
Protein kinases transfer phosphate groups from ATP to protein.
A cascade
A stream that flows in an arrange
or a number of devices or objects
in a series or sequence.
A
phosphorylation
cascade

Multiple steps of signal transduction greatly amplify the
signal. In each step the number of activated products is much
greater than one step before.

Multiple steps also provide different points, at which the
response can be regulated and also provide a specificity of
cell signaling and coordination.
Small molecules and ions as second
messengers
Nonprotein molecule, which can be
spreaded by diffusion cAMP and
calcium ions
Protein are sensitive to
the cytosolic concentration
of one or other.
Second messengers: calcium ions
and Inositol Triphosphate
Neurotransmitters, growth factors, hormones induce cells
responses via signal transduction pathways that increase the
concentration of calcium ions.
Responses: muscle contraction, secretion of substances, cell
division
Second messengers: inositol triphosphate and
diacylglycerol
Responses:
The end of pathway may occur in the nucleus or in the cytoplasm =
the change of transcription or cytoplasmic activities.

Response in nucleus is the regulation the activity and synthesis -
transcription factors

Nuclear
response to a
signal
Cytoplasmic
response to
the signal
Signaling molecules
1. Steroid hormones

This class of molecules diffuse across the plasma membrane and bind
toreceptors in the cytoplasm or nucleus. They are all synthesized from
cholesterol.

They include sex steroids (estrogen, progesterone, testosterone)
corticosteroids (glucocorticoids and mineralcorticoids)

Thyroid hormone, vitamin D3, and retinoic acid have different structure
and function but share the same mechanism of action with the other
steroids.

Steroid Receptor Superfamily. They are transcription factors that
function either as activators or repressors of transcription.
2. Nitric oxide (NO) and Carbon Monoxide (CO)

NO, a simple gas, is able to diffuse across the membrane, and alters the
activity of intracellular target enzymes. Its extremely unstable, so its effects are
local. Ex. It signals the dilation of blood vessels.

Mechanism.
Acetylcholine is released from the terminus of nerve cell in the blood
vessel wall. The endothelial cells are stimulated to produce NO (from arginine),
which causes an increased synthesis of GMP, a second messenger responsible for
blood vessel dilation.
Ach
Nerve cell endothelial cell
NO GMP Vessel dilation
AchR
3. Neurotransmitters

They signal from neuron to neuron or from neuron to other target cell
(ex. muscle cell ).

Acetylcholine
Glycine
Glutamate
Dopamine
Epinephrine
Serotonin
Histamine
GABA.

Common features: hydrophilic molecules that bind to cell surface receptors.
The binding induces conformational changes that open ion channels
ion fluxes in the cell.
Active NMDA
Receptor
Glycine Ca++ Glutamate
Inactive NMDA Receptor
Homocysteine
TCE
4. EICOSANOIDS

This class of lipids act as signaling molecules that bind to cell surface
molecules.
They include: PROSTAGLANDINS
PROSTACYCLIN
TROMBOXANES
LEUKOTRIENES.

The eicosanoids are rapidly broken down and therefore act in autocrine or
paracrine pathways. They stimulate a variety of responses in their target
cells, including blood platelet aggregation, inflammation, and smooth
muscle
contraction.

Eicosanoids are synthesized from arachidonic acid. The first enzyme involved
in their synthesis (cyclooxygenase, COX) is the target of ASPIRIN.

Aspirin actions:
-reduces inflammation and pain (inhibition of prostaglandins)
- reduces platelet aggregation and blood clotting (tromboxanes)


Applications:


- prevention of strokes
- reduce the frequency of colon cancer
AA
COX aspirin

P

T



Next lecture:
Talking and
Listening cells