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the sequence of molecular events & chemical reactions that lead to a cell's response to a signal
signal transduction pathway
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Cellular signals can come from __
- the environment: physical & chemical - (sensory systems)
- neurotransmission: chemical & electric (gap junctions)
- endocrine system: hormones
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steps in ligand-gated ion channel
- 1. Neurotransmitter binds. (ex. ACh)
- 2. Channel opens.
- 3. Ions flow across membrane.
(page 46 & 52 on slide)
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cellular responses
- signal is amplified
- A protein that binds to DNA is activated.
- Expression of one or more genes is turned on or off.
- cell activity is altered
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types of plasma membrane receptors
- ion channels
- protein kinase receptors (tyrosine kinases)
- g protein-linked receptors
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type of channel that involves an activation & inactivation gate
voltage-gated (Na+) channel
Na+ flows in when activation gate is open.
(page 53 on slide)
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__ involve calcium binding to calmodulin. Calcium/calmodulin activates a __
NMDARs; kinase
(page 55 on slide)
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ligand-binding activates a g-protein
g-protein coupled receptors
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Protein kinases are enzymes that transfer a __ from __ to one or more sites on particular proteins.
phosphate group; ATP
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__ often act in a chain __ a series of phosphorylation reactions (phosphorylation cascade) to pass a signal along.
Protein kinases; catalyzing
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__ of a target protein (substrate) stimulates or inhibits its activity. This change in activity brings about the __
Phosphorylation; cellular response
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An increase in the magnitude of each step occurs as a signal transduction pathway proceeds is a phenomenon called __
amplification
Once activated, each enzyme can activate hundreds of proteins including other enzymes that enter the next step in the pathway.
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molecules that relay signals from membrane receptors to targets inside the cell
second messengers
examples:
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__ are enzymes that chemically add a phosphate group to target proteins (substrates). This process of adding a phosphate is known as __
Protein kinases; phosphorylation
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__ are enzymes that remove a phosphate group from its substrate. This process of removing a phosphate is called __
Phosphatases; dephosphorylation
often oppose the action of kinases & ends the phosphorylation cascade
(page 60 on slide)
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g-proteins & their functions
- Gs: activates the cAMP dependent pathway
- Gi: inhibits the production of cAMP
- Gq/11: stimulates phospholipase C
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cAMP (activated by Gs) has 2 major target types:
- binds to ion channels in many kinds of sensory cells & opens the channel
- binds to protein kinases (PKA) in cytoplasm - this exposes the active site & starts a protein kinase cascade
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how cAMP signaling opens ion channels in response of nervous system cells
example: sense of smell
- Odorant molecules bind to receptors in the nose & a Gs protein is activated.
- This activates adenylyl cyclase to catalyze formation of cAMP, causing depolarization, which opens ion channels.
- Influx of Na+ & Ca2+ stimulates nerves to send signals to the brain.
(page 69 on slide)
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__ is a second messenger derived from phospholipids in the plasma membrane, hydrolyzed by phospholipases
PIP2
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__ bind to nonpolar ligands that can cross the plasma membrane. Binding to a ligand causes the receptor to __ - allows it to enter the __, where it affects gene expression.
Cytoplasmic receptors; change shape; nucleus
(Receptor may be bound to chaperonin; binding to the ligand releases the chaperonin, allowing it to enter. also needs nuclear localization signal to enter the nucleus.)
(page 75 on slide)
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The extracellular signal molecule that binds to the transmembrane receptor is the __, which activates the receptor. (Step 1)
first messenger (ligand)
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When the __ activates the transmembrane receptor, it activates the G protein by causing it to __ (Step 2 & 3)
first messenger (ligand); undergo conformational change, release GDP (inactive form) & bind GTP (active form)
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The GTP-bound (alpha) subunit of the G protein __. (Step 4 & 5)
breaks off & shuttles over to the effector
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The activated __ generates second messengers, which directly or indirectly activate __ (Step 6)
effectors; protein kinases (PKA)
- ex of effectors: adenylyl cyclase, phospholipase C
- ex of 2nd messengers: cAMP, IP3, DAG
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Protein kinases elicit the cellular response by __ (Step 7)
adding phosphate groups to specific target proteins (phosphorylating)
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As long as a G-protein coupled receptor is __, the receptor keeps the G protein active. The activated G protein, in turn, keeps the __ active in generating __
bound to a first messenger (ligand); effector; second messengers.
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If the first messenger (ligand) is released from the receptor, or if the receptor is taken into the cell by endocytosis, what would happen to the G-protein & the response pathway?
GTP is hydrolyzed to GDP, which inactivates the G-protein. The effector then becomes inactive, turning "off" the response pathway.
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The effector that produces the second messenger, cAMP, is the enzyme __ which converts __ to cAMP. __ converts cAMP to __
- adenylyl cyclase;
- ATP;
- Phosphodiesterase (continuously active in the cytoplasm);
- AMP
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Describe the Gs pathway to PKA. (all steps)
- 1. Ligand binds to transmembrane receptor, activating receptor.
- 2. Receptor undergoes conformational change, activating the Gs protein, which releases GDP & binds GTP.
- 3. The GTP-bound (alpha) subunit breaks off & shuttles over to adenylyl cyclase (the effector), activating it.
- 4. Activated adenylyl cyclase converts ATP to cAMP.
- 5. cAMP binds to regulatory subunit of PKA.
- 6. allowing catalytic subunit of PKA (protein kinases) to begin process of phosphorylation.
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What happens when phosphodiesterase binds to cAMP?
converts cAMP to AMP. cAMP can no longer bind to regulatory subunit. Catalytic subunit is no longer activated making it unable to phosphorylate
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Describe the Gi pathway.
Same primary steps as Gs, except when the alpha subunit breaks off & shuttles over to adenylyl cyclase, it inhibits production of cAMP, creating less cAMP binding to regulatory subunit of PKA, making the catalytic subunit phosphorylate less
(Gi usually found with AcH & Gs with Ne)
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An enzyme (effector) called __ breaks __ into IP3 & DAG when activated.
phospholipase C; PIP2
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Describe the Gq/11 receptor-response pathway after the ligand binds & Gq/11 is activated.
- 1. GTP-bound (alpha) subunit breaks off and shuttles over to phospholipase C (the effector), activating it.
- 2. Phospholipase C then breaks PIP2 to IP3 & DAG (second messengers).
- 3. DAG is hydrophobic & remains in the plasma membrane.
- 4. IP3 diffuses through the cytoplasm & binds to IP3 receptor on ER, releasing the stored Ca2+ into the cytoplasm.
- 5. Both DAG & Ca2+ activates PKC (protein kinase cascade), causing phosphorylation.
Note that PKC can be activated by either DAG or Ca2+ released by IP3 alone.
(page 72 on slide)
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What does GTPase do and what happens when its activity is enhanced?
convert GTP (active form) into GDP (inactive form)
produces LESS activity of G-protein signaling pathway leading to less phosphorylation
(page 78 on slide)
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What happens when GTPase activity is blocked?
GTP does not covert to GDP. GTP stays on alpha subunit. This leads to INCREASED activity of G-protein signaling pathway leading to more phosphorylation.
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binding of a signal molecule to this type of receptor turns on the receptor's built-in protein kinase & initiates autophosphorylation
receptor tyrosine kinases
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pair of monomers bonded together
dimer
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when a protein kinase phosphorylates the parter monomer in the dimer
autophosphorylation
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steps in receptor tyrosine kinases
- 2 receptor molecules each bind to a signal molecule
- move together in the membrane and assemble into a dimer
- The protein kinases of each receptor monomer are activated by a dimer formation.
- Autophosphorylation occurs.
- The multiple phosphorylations activate many different sites on the dimer.
(page 74 on slide)
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One messenger molecule binding to one receptor eventually leads to __
phosphorylation of millions of proteins.
(page 79 on slide)
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