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Cell Signalling

This document discusses cell signaling and signal transduction pathways. It describes the different methods cells use to communicate, including extracellular signal molecules that bind to cell surface or intracellular receptors to alter cell behavior. Two main types of receptors are G protein-coupled receptors and enzyme-linked receptors. These receptors activate intracellular signaling pathways using second messengers like cAMP to elicit rapid or slow cellular responses. The document outlines several key signal transduction pathways involving G proteins, cAMP, and receptor tyrosine kinases.

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Lemar Nawabi
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206 views8 pages

Cell Signalling

This document discusses cell signaling and signal transduction pathways. It describes the different methods cells use to communicate, including extracellular signal molecules that bind to cell surface or intracellular receptors to alter cell behavior. Two main types of receptors are G protein-coupled receptors and enzyme-linked receptors. These receptors activate intracellular signaling pathways using second messengers like cAMP to elicit rapid or slow cellular responses. The document outlines several key signal transduction pathways involving G proteins, cAMP, and receptor tyrosine kinases.

Uploaded by

Lemar Nawabi
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as DOCX, PDF, TXT or read online on Scribd
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Lemar Nawabi

13135552
Bachelor of Pharmacy
Cell Signalling
-

To understand the principle of cell communication and signal


transduction pathways

The different methods for sending out signal molecules between


cells
o Extracellular Signal Molecules
Communication by hundreds of signal molecules
Proteins, peptides, AA, nucleotides, steroids, retinoids,
fatty acid derivatives, dissolved gases
Hydrophobic molecules can pass across the membrane and bind
intracellular receptors
Hydrophilic molecules bind to cell surface receptors
Binding of the signal molecule (the ligand) will cause the target
cell to generate intracellular signals and alter behaviours

Lemar Nawabi
13135552
Bachelor of Pharmacy
o

Short and long distance signals

Endocrine vs Synaptic Long Distance Signalling


Endocrine Signalling
Relatively slow
Hormones very dilute in blood needs very high affinity
for receptors
Synaptic Signalling
Very fast and more precise
Can achieve high concentration in localised area only
low affinity for receptor needed
o Enables rapid dissociation and termination of
response
Gap Junctions
Narrow water-filled channels connecting cytoplasms of adjacent
cells
Direct communication bypassing the plasma membrane barrier
Two way communication allows cells to:
Homogenise intracellular conditions
Spread the effects of extracellular signals that act through
small molecule mediators e.g. Ca2+, cyclic AMP
Example:
Gap junctions in liver cells allow spread of cyclic AMP in
cells that arent connected to sympathetic nerve endings
important for release of glucose in bloodstream
Different cells can respond differently to the same signal

Lemar Nawabi

13135552
Bachelor of Pharmacy
Different response due to different intracellular machinery which
interprets and integrates the response (Same receptors)
E.g.
The neurotransmitter acetylcholine
o Decreases rate of action potential firing in heart
muscle but stimulates contraction skeletal muscle
-> different receptors
o Cells are programmed to respond to specific combinations of signals
Either survive, grow + divide, differentiate or die
The different types of receptors
o Intracellular receptors
Bind small hydrophobic molecules
Nuclear receptors
o Cell surface receptors
Act as a signal transducers (converts extracellular ligand-binding
event to intracellular signals)
Ion channel coupled receptors
G protein coupled receptors
Enzyme coupled receptors
o Nuclear receptors
Ligand-modulated gene regulatory proteins
Steroid hormones, retinoids, vitamin D
Ligands bind and alter ability of receptor to control transcription
of gene i.e. also intracellular effectors
Can also have the opposite effect of repressing transcription
o Ion-Channel-Coupled Receptors
A.K.A transmitter-gated ion channels or ionotropic receptors
Rapid synaptic signalling between nerve cells and other
electrically excitable target cells (e.g. nerve, muscle)
Multipass transmembrane protein
o G-Protein-Coupled Receptors (GPCR)
Senses molecules outside the cell and activate intracellular
signal transduction pathways
Indirectly regulates the activity of another membrane-bound
target protein (usually an enzyme or ion channel)
The G-protein (trimeric GTP-binding protein) mediates the
interaction between an activated receptors and the target
protein
GPCRS are multipass transmembrane proteins (7TM domains)
o Enzyme-Coupled Receptors
Can either function directly as enzymes or associate with
enzymes that they activate
Usually single-pass transmembrane proteins with ligand binding
site on the outside and their catalytic or enzyme activating site
on the inside

Lemar Nawabi
13135552
Bachelor of Pharmacy
Most are protein kinases or associate with protein kinases
- Second messengers
o Second messengers
Intracellular signalling molecules relay signals received at the
surface (by GPCRs or enzyme-coupled receptors) to the cell
interior
Small intracellular signalling molecules are called second
messengers, the first messengers are the extracellular signals
Signal passed on by binding to and altering intracellular
signalling proteins or effector proteins
E.g. cyclic AMP, Ca+, diacylglycerol (DAG)
o Intracellular signalling proteins can act as molecular switches
Switch from inactive to active conformation when receiving a
signal
Two important classes of molecular switches depend on the gain
or loss of phosphate

Slow

and Rapid responses to Signals


Changes to gene expression take time to exert their effect
Changes to movement secretion, metabolism, etc. are quick
E.g. Rapid phosphorylation of effector molecules
Synaptic responses are the quickest - miliseconds
Some systems generate both rapid and slow responses allows
both quick response + long term solution
Positive and Negative Feedback Loops
Positive
Output stimulates its own production
Steep or all-or-none response
Can persist after signal drops
Negative
Output inhibits its own production

Lemar Nawabi

13135552
Bachelor of Pharmacy
Counteracts so limits level of response
Short delay, brief abrupt response
Long delay, oscillations

The role that G protein-coupled receptors and enzyme-linked


receptors play in signal transduction
o Signalling through GPCRs and second messengers
Largest family of cell-surface receptors
Humans have more than 700 GPCRS
The same signal molecule can activate many GPCRs
E.g. Adrenaline activates 9 different ones
Half of all known drugs work through GPCRs or the signalling
pathways they activate
Trimeric G protein relays signals from GPCR
Some GPCRs regulate the production of cAMP
o G protein activation
Some G proteins regulate the production of cAMP
Adenylyl cyclise activation
cAMP production
cAMP exerts its effects on cAMP-dependent protein kinase (PKA)
activation phosphorylates specific serines or threonines on
selected target proteins
cAMP degraded to 5-AMP by cAMP phosphodiesterase
Reverses PKA activation
o Signalling through GPCRs and second messenger

cAMP can also alter gene expression


Target genes contain cAMP response element (CRE) in the
regulatory domains of DNA
Catalytic subunits of PKA enter nucleus and phosphorylate CREbinding protein (CREB)

Lemar Nawabi

13135552
Bachelor of Pharmacy
CREB recruits transcriptional activator CREB-binding protein
(CBP)
Some responses to cAMP occur in seconds but those that
depend on changes in gene expression can take hours
Signalling through enzyme-coupled cell-surface receptors
Like GPCRs enzyme-coupled receptors are transmembrane
proteins with a ligand binding domain on the outer surface
Each enzyme-coupled receptor subunit has only one
transmembrane domain
The cytosolic domain will have intrinsic enzyme activity or it will
associate directly with an enzyme
GPCRs and enzyme-coupled receptors activate some of the
same pathways

Receptors Tyrosine Kinases (RTKs)


Activate RTKs phoshporylate themselves
Many extracellular and cell-surface-bound signal proteins act
through RTKs
Approx 60 genes encode human RTKs
16 structural subfamilies
RTK activation

Lemar Nawabi
13135552
Bachelor of Pharmacy

o
o

Ligand binding causes RTK to dimerise bringing the two kinase


domain close together
Cross phosphorylate each other on multiple tyrosines
(transautophosphorylation)

Phosphorylated tyrosines serve as docking sites for intracellular


signalling proteins
Phosphorylation
Within kinase domain increases kinase activity
Outside kinase domain creates high-affinity docking sites
for specific signalling proteins
Serves as a switch to trigger the transient assembly of a
signalling complex that can relay the signal onward
Proteins with SH2 domains bind to phosphorylated tyrosines
E.g. platelet derived growth factor receptor
GTPase Ras mediates signalling by most RTKs

Ras superfamily consists of monomeric GTPases


Activated Ras activates other internal signal proteins
E.g. Ras activates MAP kinase signalling proteins

Lemar Nawabi

13135552
Bachelor of Pharmacy
Phosphorylation cascades stimulation of cell
proliferation, differentiation and regulation of gene
expression

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