Term
| What are the three basic steps to cell signaling? |
|
Definition
1. Reception
2. Transduction
3. Response |
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Term
| Broadly, how do effectors generate intracellular signals? |
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Definition
| Via selective phosphorylation of intracellular proteins on protein hydroxyl groups (on serine, threonine, tyrosine) |
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Term
| Are receptors always on the plasma membrane? |
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Definition
| No, they can be intraceullar, especially if the receptor is lipophillic |
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Term
| List three properties of receptor binding |
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Definition
1. Specificity to ligand
2. Saturability
3. Affinity (range of biological response is comparable to range of binding strength) |
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Term
What is the equation for Ka for receptor binding?
How does Ka relate to kon and Kd? |
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Definition
Ka
= [RL]/[R][L]
=kon/koff
=1/Kd |
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Term
| How is a receptor-ligand binding curve determined? |
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Definition
| By radioactive labeling of ligand then straining the RL (bound hormone) and determining the concentration |
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Term
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Definition
| The binding maximum for RL (receptor-ligand) |
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Term
| Describe the three lines on a receptor-ligand binding curve? |
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Definition
| Total binding, specific binding, non-specific binding |
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Term
| What is a Scatchard plot? |
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Definition
| An inversed RL binding curve that allows for calculation of Kd
(don't need to know how to calculate) |
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Term
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Definition
| The dissociation constant for RL binding
The lower the Kd, the stronger the binding |
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Term
| Define amplification as it relates to RL binding |
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Definition
| When enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade |
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Term
| Define desensitization/adaptation as it relates to RL binding |
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Definition
| Receptor activation triggers a feedback circuit that shuts off the receptor or removes it from the cell surface |
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Term
| Define integration (as it relates to RL binding) |
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Definition
| When two signals have opposite effects on metabolic characteristics such as the concentration of a second messenger X, or the membrane potential Vm, the regulatory outcome results from the integrated input from both receptors |
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Term
|
Definition
| A drug that mimics the action of a naturally occurring substance that binds to a receptor and triggers a response |
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Term
|
Definition
A receptor ligand or drug that doesn't provoke a biological response itself, but binds receptors and blocks or dampens responses of agonists or inverse agonists
"have affinity but no efficacy" |
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Term
| Give an example of an antagonist used medically |
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Definition
Remcade drugs make fake TNFα receptors, to bind ligand
Enbrel blocks the original TNFα receptors
Both lead to lower inflammation |
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Term
| What are the six general types of signal transducer receptors? |
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Definition
1. G protein
2. Tyrosine kinase
3. Guanylyl cyclase
4. Adhesion receptor (integrin)
5. Gated ion channel
6. Nuclear |
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Term
| Describe how nicotinic acetylcholine receptors open |
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Definition
| When acetylcholine binds, the M2 helixes twist, allowing the smaller subunits to face inward- opening the channel |
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Term
| What is the most common activity found intrinsic to transmembrane receptors? |
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Definition
| Tyrosine kinase (PTK) activity |
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Term
| Is cytokine receptor association with PTK reversible or irreversible? |
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Definition
| The binding is noncovalent, and therefore reversible |
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Term
| What are physical characteristics found in all tyrosine kinase receptors? |
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Definition
1. All transmembrane
2. Carboxy-terminal extracellular domain interacts with substrate
3. All have phosphorylation sites on the intracellular side |
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Term
| How is the insulin tyrosine kinase receptor unusual? |
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Definition
| Instead of one domain, it is a tetramer linked by disulfide chains |
|
|
Term
| How is a tyrosine kinase receptor activated? |
|
Definition
It dimerizes with another receptor, the two chains phosphorylate each other
This creates phosphorylation sites for SH2 domains |
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Term
| What is the function of a protein with SRC homology-2 domains? |
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Definition
These SH2 proteins are directly phosphorylated by tyrosine receptors
They
1. Recruit binding partners
2. Further facilitate PTK activation |
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Term
| What two pathways do PTKs activate? |
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Definition
1. Phosphatidylinosite 3-kinase (PI3K) pathway
2. Phospholipase C-γ (PLC-γ) pathway |
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Term
| List the steps of the insulin receptor cascade |
|
Definition
1. Insulin binds to tyrosine receptor
2. IRS-1 activated
3. IRS-1 binds to SH2, Sos, Grb, and Ras
4. Activated Ras binds to Raf-1
5. Raf-1 activates the MAP kinase cascade
6. MEK activates ERK
7. ERK travels to nucleus and activates transcription factors and SRF to translate growth factors |
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Term
| What proteins does IRS-1 bind to in order to activate Raf-1? |
|
Definition
SH2, Sos, Grb, and Ras
(Ras does the actual phosphorylating of Raf-1) |
|
|
Term
| What is the function of Raf-1? |
|
Definition
|
|
Term
| What is the function of MEK? |
|
Definition
| To move into the nucleus and activate transcription factors (such as EK1) and growth factors (such as SRF) that activate translation |
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Term
| List the steps of the PI-3K/ PKB pathway |
|
Definition
1. Insulin receptor activates IRS-1
2. IRS-1 activates PI-3K
3. PI3K converts PIP2 to PIP3
4. PIP3 activates PKB
5. PKB stimulates GLUT4 and inactivates GSK3
6. GSK3 no longer inactivates glycogen synthase |
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|
Term
| How is PIP2 converted to PIP3? |
|
Definition
| PI3K phosphorylates the C-3 hydroxyl on PIP3 |
|
|
Term
| What are the functions of the activated PKB? |
|
Definition
a) Stimulates GLUT4 glucose transporter to move to membrane
b) Inactivates GSK3 |
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|
Term
| What is the function of GSK3? |
|
Definition
| To inactivate glycogen synthase by phosphorylation, preventing Serine inhibiting glycogen synthase |
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|
Term
| How is the PI-3K/PKB pathway stopped? |
|
Definition
| A lipid phosphatase, PTEN, degrades PIP3 back to PIP2 |
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|
Term
| Why is PTEN considered an "oncogene"? |
|
Definition
Mutations in PTEN are found in many cancers
(PTEN is responsible for ending the PI-3K/PKB pathway) |
|
|
Term
| List some metabolic functions of insulin carried out via the PI-3K/PKB pathway |
|
Definition
1. Glycogen synthesis
2. Lipid synthesis
3. Glucose transport into cells |
|
|
Term
|
Definition
| A protein kinase (activated by ERK in the insulin MAP kinase cascade) that phosphorylates "S6" in the small ribosomal subunit, stimulating translation |
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|
Term
|
Definition
| An anti-cancer antibody that is antagonistic to human epidermal growth factor (Her2) |
|
|
Term
|
Definition
| An anti-cancer antibody that is antagonistic to epidermal growth factor |
|
|
Term
|
Definition
| An anti-cancer antibody that is antagonistic to vascular endothelial growth factor (to treat colorectal cancer) |
|
|
Term
|
Definition
| A small molecular inhibitor (unusual) treatment for cancer that is antagonistic to certain tyrosine kinases involved in leukemia and gastrointestinal stromal tumors |
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Term
| Describe the JAK-STAT tyrosine kinase pathway |
|
Definition
An example of a receptor that "borrows" tyrosine kinase
Receptors for EPO, prolactin, and GH
Atypical in that the ligand-binding component also binds JAK |
|
|
Term
| What are the two main G-protein second messenger systems? |
|
Definition
|
|
Term
| How much of the genome is involved with G proteins? |
|
Definition
2.3%
The largest single family of integral membrane receptors |
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Term
| Describe how G-protein coupled receptors are drug targets |
|
Definition
30% of drugs on the market are involved with GPCRs
These include antihistamines, SSRIs, antihypertensives, beta blockers, cancer treatments, and hormone antagonists |
|
|
Term
| Describe the receptor that activates G-proteins |
|
Definition
AKA G-protein coupled receptor
A trimeric, 7-pass "serpentine" receptor that mediates GTP exchange
The Gs subunit mediates the interaction between receptor and catalytic cyclase |
|
|
Term
| What are the three subunits of G proteins? |
|
Definition
|
|
Term
| Where on the G protein is the guanosine binding site? |
|
Definition
|
|
Term
| What does a G protein bind in its inactive state? |
|
Definition
| GDP (guanosine diphosphate) |
|
|
Term
| What three steps do G proteins follow when a messenger binds to the G protein-linked receptor? |
|
Definition
1. Releases GDP
2. Binds a molecule of GTP
3. Becomes active |
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Term
| What happens to the three subunits of a G protein when the G protein is active? |
|
Definition
| α seperates, leaving a beta-gamma dimer |
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Term
| In the cAMP second messenger system, what does the α subunit bind to and activate? |
|
Definition
|
|
Term
| What is the function of adenylate cyclase? |
|
Definition
| Catalyzes conversion of ATP to cAMP |
|
|
Term
| What is the precursor to cAMP? |
|
Definition
|
|
Term
| In cAMP, where is the phosphodiester ring bound to the ribose? |
|
Definition
| In the 3' and 5' carbon position |
|
|
Term
|
Definition
| Protein kinase A (also known as cAMP-dependent protein kinase) |
|
|
Term
| How cAMP activate protein kinase A? |
|
Definition
| By replacing two inhibitory C subunits |
|
|
Term
| Is the cAMP pathway reversible? |
|
Definition
|
|
Term
| How is the cAMP pathway terminated? |
|
Definition
| Degragation by the enzyme cAMP phosphodiesterase |
|
|
Term
| How do G-proteins self-inhibit? |
|
Definition
| GTP bound to the Gsα subunit is hydrolyzed by an intrinsic GTPase, turning itself off |
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|
Term
| Why is cAMP considered a signal amplification pathway? |
|
Definition
At every level, there is a ten-fold amplification
One epinephrine-receptor binding can lead to 10,000 moities |
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|
Term
| What are some metabolic effects of the epinephrine-induced cAMP pathway? |
|
Definition
Activates glycogen phosphorylase
Inactivates glycogen synthase
Stimulates gluconeogenesis
Mobilizes fatty acids |
|
|
Term
Name an epinephrine agonist and an epinephrine antagonist. (β-blockers)
Are they strong binders? |
|
Definition
Agonist- isoprotenerol
Antagonist- propanolol
Both bind much stronger than epinephrine does (Much lower Kd) |
|
|
Term
| What are some practical applications of β-blockers? |
|
Definition
Antagonists for adrenaline
Treatment of hypertension, migraines, and some cardiac problems
Relief of PTSD |
|
|
Term
| What is the mechanism for cholera toxin? |
|
Definition
Cholera toxin inactivates intrinsic GTPase activity, resulting in over-active cAMP pathway of chloride channels (CFTR) in the intestine
This leads to profuse secretion of sodium and water causing severe diarrhea |
|
|
Term
| Will high, constant amounts of epinephrine lead to cAMP pathways that continue indefinitely? |
|
Definition
No, at some point the G protein is desensitized
Every level in the cAMP pathway can be desensitized |
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|
Term
| What is the precursor to diacyglycerol (DAG) and inositol triphosphate (IP3)? |
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Definition
| Inositol-4,5-biphosphate (PIP2) |
|
|
Term
| What stimulates release of calcium as a second messenger in the phosphatidylinositol system? |
|
Definition
| IP3, inositol triphosphate |
|
|
Term
| In the phosphatidylinositol system, what does the α subunit attatch to and activate? |
|
Definition
|
|
Term
| What is the amplifier enzyme for diacyglycerol (DAG) and inositol triphosphate (IP3)? |
|
Definition
|
|
Term
| What does phospholipase C do? |
|
Definition
| Catalyzes splitting of phosphatidylinositol-2 to DAG and IP3 |
|
|
Term
| What enzyme does diaglycerol (DAG) activate? |
|
Definition
|
|
Term
| Where does inositol triphosphate (IP3) trigger the release of calcium from? |
|
Definition
| The endoplasmic reticulum |
|
|
Term
| What two effects can calcium have in the phosphatidylinositol 2nd messenger system? |
|
Definition
1. Act on proteins to stimulate contraction or secretion
2. Bind to calmodulin and activate a protein kinase |
|
|
Term
| What are the two phospholipase Cs possible in the phosphatidylinositol pathway? |
|
Definition
PLCβ: in the Gq family with an activated G protein
PLCγ: in the tyrosine kinase family with an activated growth factor receptor |
|
|
Term
| How are the second messengers in the phosphatidylinositol pathway broken down? |
|
Definition
DAG is degraded by phospholipases A1/A2
IP3 is dephosphorylated to inositol, which can be reincorporated into phosphatidylinositol |
|
|
Term
| What drug can mimic DAG in activating protein kinase C? Describe it. |
|
Definition
Phorbol esters
Isolated from croton oil (Indian trees)
They are more metabolically stable and have prolonged effects |
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