13.1 - Signal Transduction Depends on Molecular Circuits
● Signal-transduction pathways → follow a similar course
1. Release of the Primary messenger
■ Primary messenger: signal molecule released by a
trigger of a stimulus such as a wound
2. Reception of the Primary Messenger
■ Membrane receptors transfer information from the
environment to a cell’s interior
● Integral membrane proteins → have intra- and
extracellular domains
● Binding site on the extracellular domain →
recognizes the ligand
● Formation of the receptor-ligand complex →
alters structure of the receptor
3. Relay of information by the second messenger
■ Structural changes in receptors → changes in the concentration
second messengers (small molecules)
● Used to relay information from the receptor-ligand complex
○ Prominent second messengers: cyclic AMP, cyclic
GMP, calcium ion, inositol 1,4,5-triphosphate (IP3), and
diacylglycerol (DAG)
■ Use of second messengers → consequences
● They are often free to diffuse to other compartments of the cell
○ They can influence gene expression and other
processes
● The signal may be amplified significantly in the generation of
second messengers
○ A low concentration of signal molecules in the
environment can yield a large intracellular signal and
response
4. Activation of effectors that directly alter the physiological response
■ Ultimate effect of the signal pathway → activate/inhibit the pumps,
enzymes, and gene-transcription factors that directly control metabolic
pathways, gene activation, and processes such as nerve transmission
5. Termination of the signal
■ Cells lose their responsiveness to new signals
■ Signalling processes that fail to be terminated properly → lead to
uncontrolled cell growth + cancer
1
,13.2 - Receptor Proteins Transmit Information into the Cell
● 3 classes of membrane receptor proteins that convey environmental information into
the cell interior
○ Seven-transmembrane-helix receptors
○ Dimeric receptors that recruit protein kinases
○ Dimeric receptors that are protein kinases
Seven-Transmembrane-Helix Receptors Change Conformation in
Response to Ligand Binding and Activate G proteins
● Seven-transmembrane-helix (7TM) receptors →
transmit information initiated by signals
○ Photons, odorants, tastants, hormones,
neurotransmitters, etc.
● 50% of the drugs we use → alter these receptors
● Mutations → cause diseases
○ Color blindness, obesity, etc.
● Structure → 7 helices that span the membrane bilayer
● Example: β-adrenergic receptor
○ Binds epinephrine (adrenaline)
■ Hormone responsible for the
fight-or-flight response
● The binding of a ligand on the outside of the cell
induces a conformational change in the 7TM receptor that can be detected inside the
cell
Ligand Binding to 7TM Receptors Leads to the Activation of G proteins
● Example: β-adrenergic receptor
○ Next step in the pathway after binding
epinophrine?
○ Conformational change in the cytoplasmic
domain of the receptor → activates a
GTP-binding protein
■ G protein
○ Activated G protein → stimulates the activity
of adenylate cyclase
■ Increases the concentration of the
second messenger cAMP by forming it
from ATP
● How do G proteins operate?
○ Unactivated state → guanyl nucleotide bound
to the G protein → GDP
■ G protein → heterotrimer
● α, β, and γ subunits
○ Gα → binds the nucleotide
2
, ○ Gα and Gγ →
anchored to the
membrane by
covalently attached
fatty acids
○ The exchange of the bound GDP for GTP →
catalyzed by the ligand-bound receptor
■ Ligand-receptor complex → interacts with the heterotrimeric G protein
→ opens the nucleotide-binding site → GDP can depart → GTP can
bind
■ Gα dissociates from Gβγ
● Transmits the signal that the receptor has bound its ligand
● A single ligand-receptor complex can stimulate nucleotide exchange in many
G-protein heterotrimers
○ Gives an amplified response
● All 7TM receptors → coupled G proteins
○ G-protein-coupled receptors
Activated G Proteins Transmit Signals by Binding to Other Proteins
● How does the G protein propagate the message that the ligand is present?
○ Example: Adenylate cyclase
■ Contains 12
membrane-spanning
helices
■ Gα protein binds to
adenylate cyclase on
the Gα surface that
had bound Gβγ when
it was in its GDP form
■ Gαs stimulated adenylate cyclase activity → increases cAMP
production
■ Net result → the binding of epinephrine to the receptor on the cell
surface increases the rate of cAMP production inside the cell
Cyclic AMP Stimulates the Phosphorylation of Many Target Proteins by
Activating Protein Kinase A
● Increased concentration of cAMP → affects a wide range of cellular processes
○ Enhances the degradation of storage fuels
○ Increases the secretion of acid by the gastric mucosa in the cells of the
stomach and intestines
○ Leads to the dispersion of melanin pigment granules in skin cells
○ Diminishes the aggregation of blood platelets
○ Induces the opening of chloride channels in the pancreas
● Most effects of cAMP in eukaryotic cells are mediated by the activation of a single
protein kinase → protein kinase A (PKA)
3
, ○ Kinases: enzymes that phosphorylate a substrate at the expense of a
molecule of ATP
○ PKA → 2 regulatory (R) subunits +
2 catalytic (C) subunits
○ Absence of cAMP → R2C2 complex
is inactive
○ Binding of cAMP → releases the C
subunits → activated
■ Activated PKA →
phosphorylates specific
serine and threonine
residues to alter their activity
○ cAMP cascade → turned off by cAMP phosphodiesterase
■ Converts cAMP into AMP → does not activate PKA
■ C and R subunits → rejoin to form the inactive enzyme
G Proteins Spontaneously Reset Themselves Through GTP Hydrolysis
● How is the signaling pathway initiated by activated 7TM receptors switched off?
○ Gα subunits have intrinsic GTPase activity → hydrolyze bound GTP to GDP
and Pi → deactivates itself
○ Hydrolysis reaction is slow → allows
the GTP form of Gα to activate
downstream components of the
signal-transduction pathway before it
is deactivated
○ In essence, the hydrolysis of bound
GTP by Gα acts as a built-in clock
that spontaneously resets the Gα
subunit after a short time period
○ After GTP hydrolysis → GDP-bound form of Gα
reassociated with Gβγ to reform the heterotrimeric
protein
● Ligand-bound activated receptors → must be reset as
well → prevents continuous activation of G proteins
○ Receptor-ligand interaction → reversible
○ Ligand dissociates → receptor returns to its
initial unactivated state
The Hydrolysis of Phosphatidylinositol Biphosphate by Phospholipase C
Generates Two Second Messengers
● Phosphoinositide cascade → converts extracellular signals into intracellular ones
○ Intracellular messengers → arises from the cleavage of phosphatidylinositol
4,5-bisphosphate (PIP2)
■ Membrane phospholipid
○ Binding of a protein to its 7TM receptor → activation of phospholipase C
○ Gα protein that activates phospholipase C → Gαq
4
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