Biosignaling 4: Videos & Practice Problems

Cellular signaling involves complex interactions known as crosstalk, where pathways like insulin and epinephrine influence each other. Guanoyl cyclase receptors convert GTP to cyclic GMP, activating protein kinase G, which plays a role in smooth muscle contraction. For instance, Viagra inhibits cyclic GMP phosphodiesterase, enhancing blood flow. Conversely, asthma treatments raise cyclic AMP levels to relax bronchial smooth muscle. Additionally, integrins and steroid hormone receptors facilitate cellular shape changes and gene expression, respectively, highlighting the diverse mechanisms of signal transduction and cellular response.

Biosignaling 4

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.

Here’s what students ask on this topic:

What is crosstalk in cellular signaling?

Crosstalk in cellular signaling refers to the interaction between different signaling pathways within a cell. These interactions can modify cellular responses, making the signaling network highly complex and interconnected. For example, the insulin and epinephrine pathways can influence each other, leading to integrated cellular responses. Crosstalk ensures that cells can process multiple signals simultaneously, allowing for more nuanced and coordinated responses to various stimuli. This phenomenon highlights the complexity of cellular signaling and the importance of understanding how different pathways interact to regulate cellular functions.

How does Viagra work at the molecular level?

Viagra works by inhibiting cyclic GMP phosphodiesterase, an enzyme that breaks down cyclic GMP. Normally, cyclic GMP stimulates smooth muscle contraction in the veins, including those in the penis. By inhibiting this enzyme, Viagra increases the levels of cyclic GMP, leading to prolonged smooth muscle contraction. This contraction squeezes the veins, reducing blood flow away from the penis and thereby maintaining an erection. This mechanism highlights the role of cyclic GMP in smooth muscle physiology and its regulation by phosphodiesterase enzymes.

What is the role of guanylyl cyclase receptors in cellular signaling?

Guanylyl cyclase receptors are enzymes that convert GTP to cyclic GMP upon ligand binding. This process is similar to how adenylyl cyclase converts ATP to cyclic AMP. Cyclic GMP then activates protein kinase G, which plays a crucial role in various cellular processes, including smooth muscle contraction. Unlike adenylyl cyclase, guanylyl cyclase does not require a G protein intermediary. These receptors can be membrane-bound or cytosolic, with the latter being activated by nitric oxide. This signaling pathway is essential for regulating vascular tone, platelet aggregation, and other physiological functions.

How do asthma treatments work at the molecular level?

Asthma treatments, such as beta-adrenergic agonists, work by raising cyclic AMP levels in bronchial smooth muscle cells. Cyclic AMP has the opposite effect of cyclic GMP; it relaxes smooth muscle rather than contracting it. In asthma, excessive smooth muscle contraction narrows the airways, making it difficult to breathe. By increasing cyclic AMP levels, these treatments relax the bronchial smooth muscle, opening up the airways and facilitating easier breathing. This mechanism underscores the importance of cyclic AMP in regulating smooth muscle tone and its therapeutic potential in respiratory conditions.

What are integrins and their role in cellular signaling?

Integrins are adhesion receptors that bind to the cytoskeleton and extracellular matrix components like collagen. They play a crucial role in cellular signaling by facilitating cell adhesion, migration, and shape changes. When integrins bind to their ligands, they can trigger intracellular signaling pathways that influence cell survival, proliferation, and differentiation. This interaction allows cells to respond to their external environment, making integrins essential for processes like wound healing, immune responses, and tissue development. Their ability to connect the extracellular matrix with the cytoskeleton highlights their importance in maintaining cellular structure and function.