Whether or not a hormone induces a change in a cell depends on whether that cell is a target cell, and whether or not it's a target cell depends if it has the correct receptor for that hormone. But different target cells will respond differently to the same hormone. And so here, we want to really break down how and why that works. We're going to do that by talking about signaling using different secondary messengers. Now we've already introduced the second messenger, cyclic AMP. We're going to review that here, but we're also going to add a little twist to it. And then we're also going to talk about the second messengers, DAG and IP3. So, we'll start by saying that hormones may induce different signaling cascades depending on a few things here. First, the presence of a specific receptor. Now, here, we're still talking about these GPCRs, these G protein-coupled receptors. But one hormone might actually bind to several different G protein-coupled receptors, and these different GPCRs are going to be used by different cells, and the different GPCRs will cause a different signaling cascade inside the cell. Now, one of the main things that can be different for these signaling cascades is the second messenger used. So depending on what the second messenger is in the cell, that's going to turn on or turn off different things in the cell and you'll get a different response. Now, even further down the line, we have the activity of the kinase. Often, what happens in these signaling cascades is that a kinase gets activated, and kinases go out and phosphorylate different proteins. But we may activate different kinases, and even the same kinase may have different effects in different cells. And that's just because different cells have different proteins. So, for example, the same kinase in a cardiac cell versus a liver cell is going to have a different cellular response because those cells just have different proteins inside of them. Alright. Now, to break this all down, let's go through these different signaling cascades. We'll start with the one we know, the cyclic AMP signaling. So this starts with a hormone. That hormone binds to a GPCR, that G protein-coupled receptor. The GPCR activates a G protein. The G protein diffuses across the membrane, binds to adenylate cyclase. Adenylate cyclase is then activated. When it's activated, it converts that ATP into cyclic AMP. Cyclic AMP then binds to protein kinase A. And we have several arrows coming off the bottom of that protein kinase A because it's going to go out and it's going to phosphorylate a whole bunch of different proteins in the cell, and that's going to cause that cellular response. Well, here we've talked about making cyclic AMP, but another response the cell may do is to inhibit, or we're going to say here's cyclic AMP signaling inhibition. So to break this down, we'll start going through the same way we did. We're going to have a hormone. It might be the same hormone. It's going to go out. And in a different cell, well, it's going to bind to a GPCR, but it's going to be a different GPCR. Structurally very similar, but how it responds is going to be slightly different. It's going to respond by activating a G protein, but it's a different G protein. Again, structurally similar, but it's going to work slightly differently. This G protein is going to go it's going to diffuse across the membrane and it's going to bind to adenylate cyclase. But instead of activating adenylate cyclase, I'm going to draw a little down arrow here because it's going to block the function of adenylate cyclase. Well, if adenylate cyclase is turned off, well, that means the ATP in the cell just stays ATP. It doesn't get converted to cyclic AMP. And so we have the cyclic AMP grayed out. We're not making cyclic AMP. If we're not making cyclic AMP, the cyclic AMP can't bind to the protein kinase A, and so I'm going to draw a little down arrow here to say that we're sort of shutting off that protein kinase A, and we don't have any arrows coming off around the bottom. It's not going out phosphorylating proteins. We're causing a very different cellular response, in many ways, almost the opposite cellular response because instead of making cyclic AMP, we're blocking the production of cyclic AMP. All right. Well, we may also use just completely different secondary messengers. So here we're going to look at this DAG and IP3 signaling using these two molecules as second messengers. So again, we'll have a hormone go out. It might be the exact same hormone. It's going to bind to a GPCR, a G protein-coupled receptor. It's a different GPCR, again, structurally very similar, but a different one. It's going to activate a G protein, again, structurally similar, but a different G protein. The G protein is going to go out. It diffuses across the membrane and it binds to an enzyme, but it's a different enzyme. This time it binds to phospholipase C. And phospholipase C does something completely different from adenylate cyclase. What it does is it takes this molecule PIP2 or sometimes we just call it PIP2. Now, this stands for a much longer chemical name that almost certainly you don't need to know. We'll just call it PIP2. It takes PIP2 and it breaks it into two smaller molecules, DAG and IP3. Again, these have longer chemical names that almost certainly you don't need to know. So now we have these second messengers, DAG and IP3. Well, DAG goes out and it binds to a protein kinase, but it binds to protein kinase C, a completely different protein kinase that is now activated and it's going to go out phosphorylating proteins in the cell, but it's going to be a completely different set of proteins it's phosphorylating. IP3 is going to do something different. IP3 is going to cause the release of calcium ions from stores in the cell from places like the endoplasmic reticulum. Those calcium ions will have numerous physiological responses. A major one is that they're going to turn on, sort of through a couple of steps, they're going to turn on other protein kinases. Those other protein kinases are going to phosphorylate all different sets of proteins. Alright. So here you see you can start with the same hormone. And by just changing the GPCR that it binds to, you can get very different responses in the cell. Now to look at this, I just want to look at one example. And you almost certainly aren't responsible for the specifics of this example, but I think it's illustrative. So we're going to look at epinephrine. Now epinephrine is the same thing as adrenaline, and we've been using this hormone sort of as an example as we go. Well, epinephrine is active in the fight or flight response. So one thing that happens is that during their fight or flight response, you release epinephrine, and it's going to bind to these GPCRs called beta 2 receptors. And these beta 2 receptors are expressed in bronchial smooth muscle, and your bronchioles are the airways that go down into your lungs. Well, in these bronchial smooth muscles, the beta 2 receptors set off this cyclic AMP signaling cascade, and so I'm going to draw an up arrow here. We're going to get more and more cyclic AMP in the cell. That's going to turn on protein kinase A, and that's going to result in vasodilation. Vasodilation, those airways are going to relax, they're going to get bigger, and that makes sense for a fight or a fight response. Right? If you need to run somewhere or fight something, you want your airways nice and open so you get all the oxygen you need. It's also why epinephrine is used in an EpiPen, because if you're having an allergic response and those airways are closing down, the epinephrine will cause this response and cause them to open up again. Alright. But regardless, we have epinephrine causing one response in these bronchioles, but the same hormone will go out and it will bind to a different GPCR. These alpha 2 receptors are in arterial smooth muscle. Now this is in specific arterioles that are going towards places like your skin. And in this arterial smooth muscle, these alpha 2 receptors cause a cyclic AMP response, but this is that cyclic AMP inhibition. So I'm going to draw a down arrow there. So now we're blocking the production of cyclic AMP. Well, if you block the production of cyclic AMP, you get less protein kinase A turned on. If you get less protein kinase A turned on in these cells, you get vasoconstriction, or at least it blocks the vasodilation. And now that makes sense for blood vessels going to places like your skin. If you need to run somewhere or fight something, you don't need to worry about blood in your skin. You want it in your skeletal muscle. So you're going to squeeze down on those places where you don't really need the blood to go. Alright. But we're not done. This same hormone is going to also bind to another type of GPCR called an alpha 1 receptor. These alpha 1 receptors are in the same arterial smooth muscle cells. These alpha 1 receptors cause a completely different response. They cause this IP3 and DAG signaling response, and so here I'm going to draw an up arrow because we're getting more and more IP3 and DAG in the cell. Well, this results in a whole different cellular response, a whole different set of proteins being phosphorylated here, but it's also going to cause vasoconstriction. So, before we sort of didn't block vasodilation with those alpha 2 receptors. Now we're actively constricting. And so here we're reinforcing using a whole different signaling cascade, reinforcing that cellular response, and making sure that these blood vessels really close down. So again, we have one hormone causing 3 different signaling cascades, 2 of them happening in the same cell. And so when you think of these what are relatively simple things, a hormone, a single molecule going in the blood, how does it cause different responses in all these different cellular tissues? This is how. Alright. Like always, we have an example and practice problems to follow. You should give them a try, and I will see you there.