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Week 4 Lecture 11: Cell to Cell Communication (Signal transduction pathway…
Week 4 Lecture 11: Cell to Cell Communication
Cellular processes
Require
signalling molecules
for a variety of reasons
Tell another cell what to do
Cell-to cell communication helps
maintain a stable internal environment
(homeostasis)
1.
Proliferation
Cell division
Creating, maintaining and repairing organs
2.
Apoptosis
Programmed cell death
Creating, maintaining and repairing organs
3.
Cell migration
Wound healing
Germ cell and nerve cell migration during development
4.
Morphogenesis
Cell shape changes
5.
Differentiation
Cells become
specialised
Specialised in function, or as a cell
6.
Muscle contraction
7.
Stimulate enzyme activity
Example of signals that lead to differentiation and proliferation of different blood cell types
Give rise to all (over 20) different blood cell types
From hematopoietic stem cells
1.
Bone marrow stem cells
Use of
granulocyte-macrophage colony stimulating factor
(GM-CSF) and
interleukin factor 3
(IL-3)
2.
Granulocyte-macrophage precursor cells
Use of
granulocyte-colony stimulating factor
(G-CSF),
granulocyte-macrophage colony stimulating factor
(GM-CSF) and
interleukin factor 3
(IL-3)
3.
Neutrophils
Use of
macrophage-colony stimulating factor
(M-CSF),
granulocyte-macrophage colony stimulating factor
(GM-CSF) and
interleukin factor 3
(IL-3)
3.
Monocytes/macrophages
Signal transduction pathway
Requires...
Signal
Information that a cell processes from its environment
Molecule
Heat
Light
Sound
etc...
Cells are exposed to many signals
They may have different responses to different signals
From...
Blood
Hypothalamus
Thyroid
Lungs
Various glands
Other cells
Secrete signals
Receptor
Often proteins
A cell must have a
specific receptor
to detect a specific signal
The present of a signal does NOT mean the cell will respond
Signalling molecules/
ligand
binds to a receptor
Usually causes the receptor to
change shape/conformation
Triggers a cellular response
Directly
Via one step
Indirectly
Via more than one step
A molecules on the cell's surface or within a cell that recognises and binds with specific signalling molecules that may lead to a cellular response
Basic process/steps for the pathway
1.
A signalling molecule (
ligand
– can be a
hormone
) binds to a site on a receptor
Triggers a shape change in the receptor
May create or expose an active site
The ligand itself
does not change form
, unlike a substrate binding to an enzyme
2.
Transduction
Conveying message to cell
A protein binding on the active site is
activated
from an inactive form
Sometimes, allosteric inhibitors can bind to the receptor and prevent the binding of a receptor – it DOES NOT have to be activated
Can be many steps/reactions
3.
Response (in target cell)
Effects (response to stimuli)
Short term change
e.g. increase in enzyme activity
Long term change
e.g. altered DNA transcription
The target cell has a receptor
specific
for a
specific
hormone
A sequence of molecular events that lead to a cell's response
3 different actions for a signalling molecule
1.
Hormone/endocrine action
Ligands act at a distance
Ligands are secreted by a
signal-secreting cell
Travel via a
blood vessel
(or a circulatory vessel) to bind to receptors on distant target cells or tissues
The signal CANNOT bind to
non-target cells
(no receptors for the ligand) :red_cross:
2.
Paracrine (
'beside')
action
Ligands act locally (within tissue or organ)
Ligands are secreted by a
signal-secreting cell
Travel in the
interstitial fluid
(not the blood) to bind to receptors on nearby cells – in same organ
The signal CANNOT bind to
non-target cells
(no receptors for the ligand) :red_cross:
3.
Autocrine action
Ligands act locally (within tissue or organ)
Ligands are secreted by a
signal-secreting cell
Travel in the
interstitial fluid
(not the blood) to bind to its own receptors (i.e. the receptors located on the cell that secreted the ligands)
This enables
self-regulation
The signal CANNOT bind to
non-target cells
(no receptors for the ligand) :red_cross:
Receptors (molecules) classified by location
1.
Membrane bound receptors (on cell membrane)
Functions
Activate receptor to affect the nucleus
This ALWAYS activates or inhibits RNA transcription
#
Create cellular response
Made of
3 regions
Extracellular region
Binds signalling molecule
Transmembrane region
Passes through plasma membrane
Anchors the receptor into the plasma membrane (stuck there)
A membrane bound receptor is otherwise known as a
transmembrane receptor
with an extracellular binding domain
Intracellular region
Region of enzymatic activity
Responds to a signal
e.g. via conformational change to activate a protein
Examples
1.
Ligand-gated ion channel receptor (AchR)
Direct transduction
Only a ligand and receptor are needed to get a cellular reaction
Found in nervous system or neuromuscular junctions in muscle cells
a.
Acetylcholine (Ach), a neurotransmitter, binds to
two
of the five acetylcholine receptor (AchR) subunits
b.
Ach binding causes change in shape of receptor – the channel opens
c.
The presence of negatively charged amino acid within the channel allow Na+ ions to flow from the extracellular region into the intracellular region
d.
Na+ buildup in the cell leads to
muscle contraction
2.
G-protein linked receptor (epinephrine or adrenaline receptor)
a.
One epinephrine molecule (a hormone) binds to the receptor
b.
The ligand, epinephrine, binds to the receptor, causing the receptor to change shape
d.
Guanosine diphosphate (GDP) on the G-protein is
exchanged
for guanosine triphosphate (GTP)
This
activates
one of three subunits of the G protein
d.
The G-protein splits into two, with the activated subunit containing GTP travelling through the membrane and activating an
effector protein
called
adenylyl cyclase
(also an enzyme)
A cellular response is initiated and
amplified
through many steps
1.
ATP from inside the cell is converted via adenylyl cyclase to 20 molecules of
cyclic AMP
(cAMP)
cAMP is a
second messenger
, which further transmits the signal from the
first messenger
, epinephrine
2.
20 molecules of cAMP
activates
20 molecules of
protein kinase A
(PKA)
Activated PKA
inactivates
or
inhibits
glycogen synthetase
This prevents glucose conversion back to glycogen
3.
20 molecules of PKA
activates
100 molecules of
phosphorylase kinase
(PPK)
4.
100 molecules of PPK
activates
1000 molecules of
glycogen phosphorylase
(GPP)
Releases stored glucose molecules from glycogen
5.
1000 molecules GPP
produces
10,000 molecules of
glucose-1-phosphate
6.
10,000 molecules of glucose-1-phosphate
produces
10,000 molecules of
blood glucose
This causes changes in cell function
The blood glucose produced is released by cells to fuel the
'fight or flight'
response
The glucose provides energy to initiate a response
Activation is achieved by using the energy in GTP's phosphate bond
c.
The G-protein binds to the activated receptor
e.
After activating epinephrine, GTP is
hydrolysed
back to GDP
Adenylyl cyclase and the G-protein are now
inactive
3.
Protein kinase receptor (insulin receptor made of 4 peptide chain)
Indirect transduction
via a second messenger
a.
The two α subunits bind two insulin ligands
b.
A conformational change in the β subunits causes dimerisation of the β subunits. The receptors
phosphorylate
each other
A signal is transmitted to the cytoplasm that insulin is present
c.
Protein kinase (PK) domains in the receptor's intracellular region
phosphorylates
insulin-response substrates
This triggers a
cascade
of chemical, cellular responses inside the cell, via a
second messenger
Insulin signals cells to store glucose for energy
Intracellular receptors
These are
molecules
that can move
2.
Cytoplasmic receptors
Also affects RNA transcription
e.g. the receptor for the signalling molecule
cortisol
It is lipid soluble, i.e. non-polar
a.
It crosses the plasma membrane easily
b.
Cortisol binds to a
receptor-chaperone complex
Chaperone inhibits the function of the receptor, UNLESS it receives a signalling molecule
#
e.
The cortisol-receptor complex
binds
to DNA,
activating transcription
of cellular genes
c.
The binding of the cortisol ligand
releases
chaperone via a change in receptor shape
d.
Cortisol (ligand)-receptor complex moves through the nuclear pores
e.g. the receptor for
estrogen
Needs a chaperone protein as well
3.
Nuclear receptors
Thyroxine receptor
is on the nucleus
What happens to the signal in a
normal
cell after a cell has responded?
Ras proteins
can be activated
Family of proteins
Known as
small GTPases
Small enzymes
Found in most cell types
Normal cell
1.
Inactive Ras (attached to GDP)
2.
When a
receptor
is
activated
, this leads to
second messenger signalling
3.
This activates Ras via
GDP/GTP exchange
4.
Ras, now attached to GTP, can activate other proteins, resulting in a
brief
stimulation of
cell division
5.
After a brief time, Ras
hydrolyses GTP and inorganic phosphate
, and with GDP, returns to its
inactive form
#
Ras, a
signal
is regulated/switched off under
normal conditions
Cancer cell
Mutation is Ras means the signal is NOT switched off
Its constant activation leads to
tumour formation
1.
Inactive
abnormal
Ras (attached to GDP)
2.
When a
receptor
is
activated
, this leads to
second messenger signalling
3.
This activates abnormal Ras via
GDP/GTP exchange
4.
Ras is now
permanently
attached to GTP, as it cannot hydrolysed it to GDP and Pi
5.
Ras remains permanently
activated
and causes
continuous
stimulation of
cell division
Research efforts are trying to inhibit Ras
experimently