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#18 Biochemistry Signaling I Lecture for Kevin Ahern's BB 450/550

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Published on Nov 7, 2011

1. Contact me at kgahern@davincipress.com / Friend me on Facebook (kevin.g.ahern)
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9. Course materials at http://davincipress.com/bb450.html

Signaling Highlights

1. Signaling is essential for cells in multicellular organisms to communicate with each other.

2. For the beta-adrenergic receptor, a ligand, such as epinephrine is released into the bloodstream in response to a stimulus. This molecule is called the first messenger. When it arrives at the target cell, it binds to the receptor, causing the receptor to change shape slightly. On the inside of the cell, the receptor acts on a G protein, which activates the enzyme adenylate cyclase, which, in turn, synthesizes cAMP. cAMP acts by binding to Protein Kinase A (PKA) to activate it. The activated PKA begins phosphorylating a set of enzymes, turning them on or off (depending on the enzyme).

3. Phosphorylation of proteins known as transcription factors can activate or inactivate them. When activated they will turn on transcription of specific genes in the DNA.

6. G proteins bind guanine nucleotides. G protein complexes have three subunits - alpha, beta, gamma. The alpha subunit binds to GDP or GTP. When the alpha subunit is bound to GDP, it also binds the beta and gamma subunits. The G protein complex is thus inactivated. When the beta-adrenergic receptor binds its ligand, the receptor stimulates the 'loading' of GTP onto the alpha subunit, displacing GDP and the beta and gamma units. The alpha subunit is then free to bind other target proteins.

7. G proteins have an enzymatic activity that slowly breaks down GTP to GDP within the alpha subunit. This activity is very important because it ensures that the G protein will not be left in the 'on' state permanently. When the alpha subunit is bound with GTP, it can bind to adenylate cyclase and activate it.

8. Cells have two ways of turning off the beta adrenergic receptor. The first involves simple dissociation of the epinephrine ligand from the receptor. This leaves the receptor in the 'off' state. The second method involves phosphorylation of the receptor. The phosphorylated receptor is then bound by the protein called beta-arrestin that binds the receptor and inhibits the activation of G proteins.

9. cAMP in cells acts on a kinase known as Protein Kinase A (PKA). PKA is composed of four subunits - two identical catalytic subunits (C) and two identical regulatory subunits (R). When the complex is present as C2R2, the PKA is inactive. Binding of cAMP to the R subunits causes them to dissociate from the C subunits. The freed C subunits are therefore active.

10. Signaling through the adrenergic receptor has the effect of increasing blood glucose. Insulin is a hormone that counters the effect of epinephrine. Phosphodiesterase breaks down cAMP. Inhibitors of phosphodiesterase, such as caffeine, have the effect of increasing blood glucose.

11. Other receptors involved in signal transduction (signaling) act in different ways. Some receptors stimulate the activity of the enzyme Phospholipase C. This enzyme acts on a membranous molecule called PIP2. Cleavage of PIP2 by phospholipase C results in production of TWO second messengers. One of these, DAG remains near or in the lipid bilayer where it stimulates another kinase, Protein Kinase C. Protein Kinase C acts to phosphorylate numerous proteins/enyzmes to activate/inactivate them, depending upon the enzyme. The other second messenger produced by phospholipase C cleavage is IP3. IP3 is soluble in the cytoplasm and it acts there to stimulate the release of calcium.

12. Calcium isa kind of 'third' messenger in the process of signaling. Cells normally must keep the concentration of the ion low so as to prevent it from binding to proteins and precipitating DNA. Calcium is essential for muscular contraction.

13. EF Hands are important structural domains of calcium binding proteins. Calmodulin is one such protein.

14. Calmodulin binds calcium, helping to keep its concentration relatively low. Upon binding calcium, calmodulin changes shape and this change in shape allows it to bind to other proteins that it wouldn't otherwise be able to bind to.

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