Just like cyclic AMP has a bunch of functions in the cell, G also carries out a wide variety of functions in cell signaling. In addition to activating adenylyl cyclase, G protein with GTP bound will also activate phospholipase C, which is an enzyme you might remember from the last unit. And this enzyme cleaves lipids. Hopefully, you remember specifically where it cleaves lipids, as that's something that we covered for the last exam. Now phospholipase C, in the case of cell signaling, will cleave the bond between the inositol phosphate and the glycerol of the molecule phosphatidylinositol or abbreviated as PIP2. And you can see that happening right here. We have our G protein-coupled receptor, with ligand bound, and that this little light thing saying it's that G is activating phospholipase C PLC, what we see right there. And it's going to cleave this molecule, PIP2, Phosphatidyl Inositol, and it's going to cleave it into what's abbreviated as IP3 or Inositol Triphosphate. What you see right here And it's also the other part of the molecule after it's cleaved is called diacylglycerol or DAG. So, just to recap, Phospholipase C gets activated by G and it cleaves PIP2, into DAG and IP3. Done. Just to note quickly that DAG will stay in the membrane, whereas IP3 will exit the membrane, as it is able to interact with water much better. The other part of the molecule is very hydrophobic lipid, but IP3 has those phosphate groups meaning, it's going to have a lot of charge so it can interact with water very nicely. So, inositol triphosphate will actually go diffuse into the cell and it will open up these calcium channels. So here's some sort of internal cell membrane. It's going to activate these calcium channels so that calcium gets released. And diacylglycerol and calcium, these guys will actually lead to the activation of protein kinase C. Additionally, inositol triphosphate and calcium will act as secondary messengers in a variety of other signaling pathways. But just know that calcium and diacylglycerol will activate protein kinase C. And know how the cleavage of phosphatidylinositol leads to DAG and IP3. Moving on, we've spent a lot of time on G protein-coupled receptors. Now, let's actually take a look at a different type of receptor, called receptor tyrosine kinase or RTK. And these are receptors that are capable of autophosphorylating, meaning they can phosphorylate themselves and they'll do so at tyrosine residues. And they'll do this in response to ligand binding. So we're going to look at insulin as our example of an RTK or the insulin receptor rather as an example of an RTK. And the insulin receptor actually works best as a dimer. And you can see that we have a nice protein dimer right there meaning that we have these 2 halves basically coming together to, or dimerizing, and forming this nice protein dimer that we see there acting as a receptor. And here, we have insulin. That's our ligand. And insulin is going to bind into our receptor phosphorylation cascade. So let me hop out of the image here. So what you can see happening is this is autophosphorylate. You can see here that it is autophosphorylate. You can see here that it is going to have a bunch of phosphate groups attached to it. And specifically with insulin, the insulin receptor after it is phosphorylated, it's going to phosphorylate a protein called IRS1, and IRS1 is going to turn on this RAS protein complex. So it's a complex of proteins, kind of like all bound together. IRS1 is going to turn on RAS, the RAS protein complex. The RAS protein complex phosphorylates MEK. MEK phosphorylates ERK, and ERK enters the nucleus and activates genes. So basically, insulin binds, the receptor tyrosine kinase does its autophosphorylation, and this generates a phosphorylation cascade which ultimately leads to this protein ERK entering the nucleus and activating certain genes leading to the expression of certain genes. Anyways, IRS1 also activates protein kinase B, right? So hopefully you're starting to see a pattern here that all these components of signaling pathways tend to do multiple things, right? They don't just have one simple job. So anyways, IRS1 also activates protein kinase B, and that ultimately leads to more glucose transporters, specifically GLUT4 transporter in the membrane. So let's back up and think about this for a second. So insulin is released in response to high sugar levels in your blood. So when insulin is released, it's going to bind to this receptor tyrosine kinase and activate a bunch of genes related to processing this sugar basically. Additionally, it's going to activate protein kinase B and protein kinase B is going to put these glucose receptors on the membrane to transport into the cell this high concentration of glucose that is, that is present outside the cell, right? Like in the blood. So thinking about it on a more medical level, we often say that insulin lowers blood sugar levels. Well, this is partially how it's doing that by increasing the number of glucose transporters in the membrane thereby taking sugar out of the blood and putting it in the cell. Additionally, insulin causes glycogen formation because you have this excess of sugar; you want to store some of it for later because you don't need to burn all of it right away for nutrients. So protein kinase B, in addition to causing those GLUT4 receptors to be integrated into the membrane, also leads to the activation of glycogen synthase. And the way it does that is, it actually inactivates GSK3 or glycogen synthase kinase. That's what the GSK is. So it inactivates GSK3, and that allows glycogen synthase to become active because it's now, this is where things maybe get a little confusing. So GSK3 is normally an active protein, and its job is to inactivate glycogen synthase. So normally, GSK3 is on and it's keeping glycogen synthase off. And it does this by phosphorylating it. Here's a great example of where phosphorylating something actually inactivates it. So GSK3 keeps glycogen synthase off by phosphorylating it. But when protein kinase B comes around, it phosphorylates GSK3 which inactivates GSK3. And that allows glycogen synthase to actually become active and synthesize glycogen with all that extra glucose. And remember, a lot of glucose is getting transported into the cell now because of those extra glucose transporters. So you can see how this one ligand, right? Insulin is doing a wide variety of things in the cell but they're all kind of related to this central theme of trying to do something about all that sugar. So, hopefully, that kind of helps illustrate a little bit how expansive these signaling pathways are and how they can integrate into one another. Alright. Let's flip the page.
Review 2: Biosignaling, Glycolysis, Gluconeogenesis, & PP-Pathway
Biosignaling 3