the sequence of molecular events & chemical reactions that lead to a cell's response to a signal
signal transduction pathway
Cellular signals can come from __
- the environment: physical & chemical - (sensory systems)
- neurotransmission: chemical & electric (gap junctions)
- endocrine system: hormones
steps in ligand-gated ion channel
- 1. Neurotransmitter binds. (ex. ACh)
- 2. Channel opens.
- 3. Ions flow across membrane.
(page 46 & 52 on slide)
- 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
types of plasma membrane receptors
- ion channels
- protein kinase receptors (tyrosine kinases)
- g protein-linked receptors
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)
__ involve calcium binding to calmodulin. Calcium/calmodulin activates a __
(page 55 on slide)
ligand-binding activates a g-protein
g-protein coupled receptors
Protein kinases are enzymes that transfer a __ from __ to one or more sites on particular proteins.
phosphate group; ATP
__ often act in a chain __ a series of phosphorylation reactions (phosphorylation cascade) to pass a signal along.
Protein kinases; catalyzing
__ of a target protein (substrate) stimulates or inhibits its activity. This change in activity brings about the __
Phosphorylation; cellular response
An increase in the magnitude of each step occurs as a signal transduction pathway proceeds is a phenomenon called __
Once activated, each enzyme can activate hundreds of proteins including other enzymes that enter the next step in the pathway.
molecules that relay signals from membrane receptors to targets inside the cell
__ are enzymes that chemically add a phosphate group to target proteins (substrates). This process of adding a phosphate is known as __
Protein kinases; phosphorylation
__ are enzymes that remove a phosphate group from its substrate. This process of removing a phosphate is called __
often oppose the action of kinases & ends the phosphorylation cascade
(page 60 on slide)
g-proteins & their functions
- Gs: activates the cAMP dependent pathway
- Gi: inhibits the production of cAMP
- Gq/11: stimulates phospholipase C
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
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)
__ is a second messenger derived from phospholipids in the plasma membrane, hydrolyzed by phospholipases
__ 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)
The extracellular signal molecule that binds to the transmembrane receptor is the __, which activates the receptor. (Step 1)
first messenger (ligand)
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)
The GTP-bound (alpha) subunit of the G protein __. (Step 4 & 5)
breaks off & shuttles over to the effector
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
Protein kinases elicit the cellular response by __ (Step 7)
adding phosphate groups to specific target proteins (phosphorylating)
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.
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.
The effector that produces the second messenger, cAMP, is the enzyme __ which converts __ to cAMP. __ converts cAMP to __
- adenylyl cyclase;
- Phosphodiesterase (continuously active in the cytoplasm);
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.
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
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)
An enzyme (effector) called __ breaks __ into IP3 & DAG when activated.
phospholipase C; PIP2
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)
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)
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.
binding of a signal molecule to this type of receptor turns on the receptor's built-in protein kinase & initiates autophosphorylation
receptor tyrosine kinases
pair of monomers bonded together
when a protein kinase phosphorylates the parter monomer in the dimer
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)
One messenger molecule binding to one receptor eventually leads to __
phosphorylation of millions of proteins.
(page 79 on slide)