Lecture 11
Cell Signaling
Required Reading:
• Morris text: Chapter 9
• Section 9.1 Principles of Cell Signaling
• Section 9.2 Distance Between Cells
Objectives:
• Signaling Receptors
• G Protein-coupled Receptors
• Receptor Kinases
Textbook reference sections/pages:
• Morris text – Chapter 9 (pp. 179-194)
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Section 9.3 Signaling Receptors (pp. 185-188)
Section 9.4 G Protein Coupled Receptors (pp. 188-191)
Section 9.5 Receptor Kinases (pp. 191-194)
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Interactive Activity
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Slide 2
How Do Cells Communicate?
• All cells process information from the environment
• Communication required for coordination of activities
• Communication most often via chemical signals that
bind to specific receptors
– Hormones, neurotransmitters, CO2, H+
• Signals can come from outside the organism, or from
neighboring cells; short distances or long
• Examples of molecules that act a signals:
• Plants:
– Ethylene
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• Animals:
– Epinephrine
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Receptor Activation and Receptor Types
• Receptor: protein that receives and
interprets information carried by signaling
molecule (ligand)
• Ligand binds to ligand-binding site on
receptor à conformational shape change in
the entire receptor
• Shape change activates receptor
• Receptors can be found on:
– inside the cell = intracellular receptors
– cell surface = cell surface receptors
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Intracellular Receptors
– Found inside the cell
– Receptor + ligand (if steroid) =
steroid–receptor complex
• Either in cytoplasm or nucleus
– Use non-polar signaling molecules:
• Small and pass freely through plasma membrane
• Can be a steroid
• Steroids are hydrophobic; pass through plasma membrane
• Active steroid-receptor complexes act as transcriptional
regulators and control gene expression
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Cell Surface Receptors
• General structure:
1. Ligand-binding site
2. Extracellular domain
3. Transmembrane domain
4. Cytoplasmic domain
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1
3
4
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Cell Surface Receptors (2)
• Use polar signaling molecules
– Small polar proteins, cannot cross
plasma membrane
• Types of cell-surface
receptors:
– There are thousands of different receptor proteins on
the surface of any given cell.
– Most can be placed into one of three groups,
according to the way they are activated.
• G protein-coupled receptors
• Receptor kinases
• Ion channels
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Cell Surface Receptors (3)
• Cell Surface Receptors Act Like Molecular
Switches
– Many receptors exist in two alternative states – on or off
– Signaling molecule bound to receptor à receptor
activated (i.e. on)
– Signaling molecule not bound to receptor à receptor
inactive (i.e. off)
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Signal Transduction, Response and
Termination
• Signal transduction (and sometimes amplification),
response and termination are the steps that occur
after a signaling molecule binds to receptor
– Although the ligands are different, the subsequent steps
are similar
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G Protein-Coupled Receptors
Transmembrane proteins with this general structure:
i. Ligand binding site – extracellular
ii. Transmembrane region - 7 alpha helices
iii.G-protein binding site – cytoplasmic
• Types of signal molecules used
by G-protein-coupled receptors:
• Small molecules
• Many hormones
• Neurotransmitters
• G-protein-coupled receptors
are responsible for senses of
sight, smell, taste
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Slide 10
G Protein-Coupled Receptors
• When ligand binds to G protein-coupled receptor, it is
activated
• When active, it binds to a G protein (cytoplasm)
• G proteins can be bound to either GDP or GTP
(guanine nucleotides)
• G protein + GTP = active
• G protein + GDP = inactive
• Ligand binds ¨ receptor then binds to G protein ¨
GDP replaced with GTP and G protein activated ¨
signal transmitted
– Active G protein then activates other proteins as part of
signaling pathway
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G Protein-Coupled Receptors
• Some G proteins are composed of
three subunits:
• α (alpha)
• β (beta)
• γ (gamma)
• α (alpha) subunit binds either GDP
or GTP
• α subunit + GDP à 3 subunits bound =
inactive
• Receptor activated à GDP on α
subunit replaced by GTP à 3 subunits
separate = active
• Activated α subunit binds to and
activates target protein à response
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Example of G Protein Activation and
Amplification: Adrenaline Signaling in
Heart Muscle
Target protein = adenylyl cyclase
Activated adenylyl cyclase converts
ATP to cAMP (second messenger)
cAMP = second
messenger
cAMP binds to Protein kinase A
As long as adrenaline is
bound to the receptor, the
heart rate will remain high.
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Activated protein kinase A
phosphorylates heart proteins
Heart rate increases
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Amplification of Adrenaline Signal
• A little adrenaline goes a
long way!
• Amplification occurs at
several places (1, 2, 3)
1
• Small amount of signal à
large response
2
3
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Key Point:
• Cell response depends on cell
type and proteins in it
• G protein-coupled receptors
typically activate downstream
enzymes or open ion channels
• Effects are rapid, short-lived,
reversible
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Termination of G protein Signal
• The amount of time a signaling molecule remains bound to
its receptor depends on how tightly the receptor holds on to
it, its binding affinity for the signaling molecule.
• Most ligands do not bind permanently to receptors
• Signal turns off once ligand is unbound (G protein deactivates itself)
• GTP to GDP
• Other parts of the pathway must also turn off
• Enzymes degrade cAMP to AMP
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Termination of G protein Signal (2)
• Phosphatases remove phosphate group = dephosphorylation
• When a protein is dephosphorylated by a phosphatase, it
typically becomes inactive
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Receptor Kinases
• A kinase is an enzyme that adds
a phosphate group to another
molecule ¨ phosphorylation
• Phosphate group comes from
ATP
• When a protein is phosphorylated by a kinase, that protein
typically becomes active
– Shape change or
– Provides new site for other
proteins to bind
• Recall: phosphatases have the
opposite effect i.e. remove
phosphate group =
dephosphorylation
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Receptor Kinase Activation/Transduction
• Extracellular portion - binds signaling molecule
• Intracellular portion - is the kinase
• Dimerization activates cytoplasmic kinase domains causing
them to phosphorylate each other at multiple sites on their
cytoplasmic tails.
• Phosphorylated areas provide sites for other proteins to bind
and become active.
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Receptor Kinases
Where is receptor kinase signaling used?
• Formation and elongation of limb buds that
become our arms and legs
• Wound healing
• when we cut ourselves, platelet derived growth factor
(PDGF) released from platelets in the blood signals to
cells at the wound site, triggering cell division to repair
the damage
• In general, receptor kinases initiate long-term
responses
• Activation of proteins involved in changes in gene
expression
• Cell growth, division, differentiation, shape change
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Receptor Kinase Example: The MAP kinase pathway
Paper cut – ouch!
MAP kinase pathway:
Platelets release proteins
including PDGF
PDGF binds to receptor
kinases on cell surface
Dimerization; receptor
activation
NB:
Ras + GDP ¨ inactive
Ras + GTP ¨ active
Ras protein activated (in
cytoplasm); GTP bound
Kinase series triggered;
kinase enters nucleus
Transcription regulators for
cell division activated
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This pathway becomes
inactive once the GTPbound Ras is converted
to GDP.
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Receptor Kinases
• A receptor kinase, Kit, responsible for the production of
pigment in skin, feathers, scales and hair
• Mutations in the Kit receptor kinase causes patterns of
incomplete pigmentation (white patches)
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Ligand-gated Ion Channels
• These are receptors that alter
flow of ions across plasma
membrane (channels)
• Conformational shape
change opens channel
– Allows flow of ions in and/or out
– Channel remains open as long
as the signaling molecule
remains bound
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Integration of Signaling Pathways
• Signaling pathways do not operate independently –
signaling is very complex!
– In one organism - many different signaling molecules
each with own receptors
• Different signaling molecules can bind to a single cell
and activate several signaling pathways simultaneously
– final response of a cell depends on how the pathways
intersect with one another
• Also, one signal may inhibit signaling pathway
triggered by a another signal and weaken the end
response
• “Molecular cross-talk”
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