Because signals don't exist in a vacuum, they coexist within the cell. They interact with each other and modify cellular response. This phenomenon is called crosstalk, where the signals are 'talking' to one another. You can see a simple example of that happening here with our insulin pathway and our epinephrine pathway. You can see that there's going to be some crosstalk right here. This is a very simplified image of it. Right next to it, you can see that it can get far more complicated. Here, we're seeing the integration of many different signals all going on. Again, this isn't even a complete picture. There's way more going on in the cell all the time. Hopefully, this image can give you a sense of how complex and interconnected these various signaling pathways are.
Now, there's another type of receptor we haven't talked about yet, and that is the guanylyl cyclase receptor. This is a receptor enzyme that is going to convert GTP to cyclic GMP. Does that sound familiar? Yes, because it's just like adenylyl cyclase, except now instead of ATP to cAMP, we're doing GTP to cyclic GMP. And of course, this happens in response to ligand binding. The difference here is that with adenylyl cyclase, it's actually activated by protein G, which is turned on by ligand binding. With these receptors, ligand binding actually activates the guanylyl cyclase to convert GTP to cyclic GMP. There's no protein G intermediate going on in this interaction. Most of these receptors are membrane-bound, but there is one cytosolic guanylyl cyclase that we know about, and that one is activated by nitric oxide—a little fact there.
Cyclic GMP stimulates the protein kinase G cascade. Protein kinase G is activated by cyclic GMP, which is why it's named so. Interestingly, nitric oxide, the ligand that activates the cytosolic guanylyl cyclase, is derived from arginine and oxygen. It causes smooth muscle contraction. Viagra also affects smooth muscle contraction because it inhibits cyclic GMP phosphodiesterase. With cyclic AMP, we have phosphodiesterase that breaks it down to help control the signaling pathway. Similarly, there's a phosphodiesterase that breaks down cyclic GMP to help regulate the signal. Therefore, cyclic GMP stimulates smooth muscle contraction of the vein leaving the penis. Viagra inhibiting the phosphodiesterase that breaks it down means there's going to be a lot of cyclic GMP present, meaning there's going to be a lot of stimulation of the smooth muscle on that vein. Contracting the smooth muscle on the vein will squeeze the vein, limiting blood flow out and away towards the heart, meaning more blood is going to stay in that area and lead to an erection. It's a real-world application of this stuff we're talking about.
Asthma is similar in that it is an immune response that causes smooth muscle contraction in the bronchia. Unlike what Viagra does, with asthma, we actually use a beta-adrenergic agonist that raises cyclic AMP levels, and cyclic AMP does the opposite of cyclic GMP. So by elevating cyclic AMP levels, we relax the smooth muscle, which opens up the airways and lets you breathe.
Moving on, there are two more receptor types we need to mention. First are the adhesion receptors called integrins. They bind to the cytoskeleton and collagen in the extracellular matrix. When these proteins change position, the cells can change shape and form. You have your cytoskeleton here, and this integrin is going to bind the cytoskeleton and collagen in the extracellular matrix. Think of this as a structural receptor that leads to the cell changing shape and form.
Lastly, we must mention the steroid hormone receptors. Unlike the receptors we've been talking about that are located on the membrane, steroid hormone receptors are inside the cell. Steroids as a ligand can easily diffuse through the membrane because they are readily lipid soluble. They actually need a transporter to move through the blood. Steroids have a backbone of sterol, which is super lipid soluble. Inside the cell, they bind to their receptor. Generally, these receptors act as transcription factors. Here we see the binding of a steroid hormone to its receptor, which then dimerizes, enters the nucleus, binds to the DNA, and acts as a transcription factor for gene expression. Some steroid hormones have their receptor inside the nucleus, depending on the hormone.
