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32 Cards in this Set
- Front
- Back
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Describe the G protein cycle
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A ligand bound GCPR induces dissociation of GDP from the alpha subunit so that GTP which is in higher concentrations can bind. GTP binding then causes dissociation of the alpha from the beta-gamma subunit. Free alpha and beta-gamma subunits can then bind to and regulate downstream signaling proteins (effectors).
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What is termination? How does it work?
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The alpha subunit has an intrinsic GTPase activity that cleaves the GTP to GDP and terminates the signal. Often, there are protein modulators called GAP's (GTPase accelerating protein).
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What are monomeric G proteins?
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They are G proteins, which are acted upon by intracellular Guanine exchange factors, not the cell surface GEF's (GPCR)
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What are the four major families of Heterotrimeric G protein?
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Gs, Gi, Gq, G12
***There exists several types of each subunit, so many combinations are possible |
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How is each heterotrimer named?
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Based on the identity and function of the alpha subunit.
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What is the function of alpha - s?
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Stimulates adenylyl cyclase thus increasing the cells level of cAMP.
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What is the function of alpha - i?
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Inhibit adenylyl cyclase, thus decreasing cellular levels of cAMP.
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What is the function of alpha - q?
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They activate phospholipase C which then generates IP3 and DAG.
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What is the function of alpha - 12?
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They activate Rho-guanine-nucleotide exhange factors, leading to increased signaling via the Rho monomeric G protein.
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What is the function of Beta-gamma subunits?
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They regulate ion channels as well as many of the same effectors as are regulated by alpha subunits.
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How does cholera toxin affect the G protein process?
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It colvently modifies the alpha - s subunit with an ADP-ribosylation. This makes it so alpha - s cannot hydrolyze GTP and is stuck in the active state. Prolonged levels of cAMP are produced in intestinal epithelial cells. Increased cAMP causes a large efflux of water into the gut and diarrhea.
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What are the function of phosphodiesterases?
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They degrade cAMP.
***Multiple phosphodiesterases exist. Some degrade cAMP and cGMP, some only cAMP or cGMP. |
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What is the function of cAMP?
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It targets Protein Kinase A (PKA), binding and activating it.
PKA has 2 regulatory and 2 catalytic subunits. cAMP binds the regulatory subunits, the catalytic subunits dissociate and become active. |
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What is PKA's function?
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It can cause rapid changes within the cell by phosphorylating important enzymes and ion channels
It can induce slow changes via modulation of transcription. |
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What is an example of PKA induced modulation of transcription?
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Activated PKA moves into the nucleus, phoshphorylates a transcription factor called cAMP response element binding protein (CREB). CREB binds a specific DNA regulatory region (CRE) found in a number of genes.
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What is the difference between Adenylyl cyclase and Phospholipase C?
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Adenylyl cyclase is a membrane spanning protein. Phospholipase C is associated with the inner membrane, but is not an integral protein.
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How is phospholipase C activated?
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alpha - q binds and activates Phospholipase C.
Beta-gamma can also activate PLC. |
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What is the function of PLC?
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It acts on a membrane lipid called phosphatidylinositol 4,5 bisphosphate. It cleaves this lipid into IP3 and DAG
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What is the function of IP3?
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It regulates the cell's concentration of calcium.
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How does IP3 work?
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It becomes water soluble when cleaved and rapidly diffuses through the cytosol to the ER where it binds IP3 receptors. It then triggers the release of Ca++ from the ER into the cytosol.
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How are IP3 induced signals terminated?
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Specific lipid phosphatases that dephosphorylate IP3.
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What is the function of DAG?
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To activate Protein Kinase C (PKC)
Binding of DAG to PKC translocates PKC from the cytosol to the plasma membrane. ***Many forms of PKC bindt o and are activated by Ca and DAG. |
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How is DAG different from IP3?
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It is not diffusible, but remains as an membrane constiuent.
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What is NO?
What is its limitation? |
Nitric Oxide
A diffusible signaling molecule It only works over a limited distance because it has a short half life |
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What is NO's major function?
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To relax smooth muscle cells.
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What was NO's formerly called?
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Endothelium-derived releasing factor (EDRF)
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How is NO involved with the relief of angina?
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Nitroglycerine is converted to NO, which relaxes the blood vessels.
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What are 2 other functions of NO?
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It helps macrophages and neutrophils to kill invading microorganisms. Also importantn for signaling between nerve cells.
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How is NO produced?
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By NO synthases that use arginine as a substrate.
They are referred to as eNOS in endothelial cells and nNOS in nerve and muscle cells. |
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What is iNOS?
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Inducible NO.
Used by macrophages only in response to infection. |
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How does acetylcholine use NO to relax smooth muscle cells?
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Autonomic nerves in the blood vessel wall releases acetylcholine --> Acetylcholine acts on a GPCR, a muscarinic acetylcholine receptor on the surface of endothelial cells that line the blood vessel wall --> The activated acetylcholine GPCR activates a G protein signaling pathway that involves alpha - q. --> Increased Ca++ then helps to activate eNOS --> eNOS increases NO levels in the endothelial cells and NO diffuses tot he nearby smooth muscle cells. --> NO directly binds and activates guanylyl cyclase to raise intracellular levels of cGMP in the smooth muscle cells. --> cGMP activates the protein kinases PKG which phosphorylates several proteins causing smooth muscle cell relaxation.
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How does viagra work?
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It inhibits a cGMP Phosphodiesterase resulting in increased cGMP which keeps the blood vessels relaxed and increasing blood flow.
***NO normally stimulates guanylyl cyclase to create cGMP. |
