>>Dr. Ketchum: In this lecture video, we will continue our discussion of membrane-bound
mediated responses, and we’re going to do that by specifically focusing on G-protein
linked receptors. And we’re specifically going to focus on the cyclic AMP second messenger
system. So in the cyclic AMP second messenger system, first off, let’s orient yourself.
So here’s the extracellular fluid in blue, in tan is the cytosol, and then we have the
plasma membrane. So rather than just memorize the pathway, look at what—who the players
are. Here we have a receptor, we have a G protein, we have adenylate cyclase, which
is the amplifier enzyme. Here is our cyclic AMP, our second messenger. We have protein
kinase, which always phosphorylates a protein. So let’s look at turning on the cyclic AMP
system now that you know who the players are. We’ll start with the ligand; remember the
ligand must be lipophobic. So the ligand is binding to the receptor in step one. Step
two then activates the G protein. And we’ve talked about what happens when you activate
a G protein: GDP falls off the alpha subunit, GTP is added, and the alpha subunit slides
over. When the alpha subunit slides over, it will smack into adenylate cyclase, your
amplifier enzyme. That will then convert ATP to cyclic AMP, your second messenger, which
then activates protein kinase A. Which then phosphorylates a protein, and it requires
energy to phosphorylate a protein, and then you get some sort of response inside the cell.
So the response inside the cell is going to come later. So when we talk about very specific
tissues, we’ll tell you exactly what that response is. We’ll need to turn off the cyclic
AMP system. The ligand, remember, has a half-life in the extracellular fluid, and so eventually
it will be degraded. The other thing is you don’t want to have the response inside of
the cell occurring forever. You want the system to have a response and then the response be
over, okay? For example if you need to increase your heart rate because you’re having a
sympathetic response, you don’t want your heart rate to stay elevated all the time;
you want your heart rate to be able to come back to normal. How do we turn off the cyclic
AMP system? So we have a few steps here. First off, remember that the ligand binding to the
receptor is reversible. So the ligand falls off the receptor. Then remember that we activated
the G protein, so now we need to deactivate the G protein. So we’re going to deactivate
the G protein by hydrolyzing GTP back to GDP plus a phosphate. So that’s a hydrolysis
reaction. Remember we converted ATP to cyclic AMP, so we want to lower the levels of cyclic
AMP in the intracellular fluid. So we’re going to use an enzyme called phosphodiesterase.
And what phosphodiesterase does—this is an enzyme that’s covalently regulates reactions,
and it will always break down a second messenger. So phosphodiesterase always breaks down second
messengers. In this case, we’re breaking down cyclic AMP. Then we also have phosphatase.
Phosphatase is an enzyme that will dephosphorylate the protein. Remember protein kinase A phosphorylated
a protein. So as long as we have that protein phosphorylated, we’ll still have a response
occurring inside the cell. So phosphatase will dephosphorylate the protein, and all
of these together then will turn off the system. Phosphatase, remember, is also covalently
regulated.