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Episode 123

Episode 123: Part 1 Signal Transduction With G Proteins With SRNA David B.

Jun 28, 2023

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You can never be too prepared when it comes to CRNA school. So why not get a head start and begin learning the concepts you are expected to learn? In today’s show, Jenny Finnell prepares for us a special Academic Series born from a conversation with a current student. RRNA David B. has observed gaps in nursing education knowledge, even when it comes to interviewing for CRNA schools. They are now bridging those gaps starting with this episode, where they dive deep into signal transduction. What is signal transduction and why does it matter? What role do G proteins play in signal transduction? Tune in to find out more key information that will help you stand out in interviews and support you in CRNA school.

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Part 1 Signal Transduction With G Proteins With SRNA David B.

We are going to talk about signal transduction. What is it and why does it matter? That’s what we are going to get into. I’ll give you a brief overview of some changes that are coming to the show. We are going to be doing this academic series. The reason why we are doing this is because David B., a CRNA School Prep Academy student, has pointed out to me that there are gaps in the nursing education knowledge even when it comes to interviewing for CRNA school and also as you transition into the role of being a current student. He has identified where these gaps are.

The concepts we are going to be talking about with David are around those concepts that he feels would be incredibly beneficial for you to not only prepare for in-depth knowledge for your interview but also as you transition into the role of an RRNA. These are all concepts that you will have to learn in school and are expected to know and understand. Why not get a headstart?

That is why we are doing these. I’m also going to preface this with some of these topics are visual topics, meaning he does it on a whiteboard where he can walk you through some of these chemical reactions and things of that nature. I do encourage you to head over to CRNA School Prep Academy’s YouTube channel, which is CRNA School Prep Academy, and follow along there. Also, to help facilitate your learning, we will have a PDF note for you to download. This way, if you are reading and you want to come back and hit a refresher, you will have some notes to go by.

That is hopefully going to facilitate. We are open to your feedback. Please. There’s an email, Hello@CRNASchoolPrepAcademy.com. Let us know how you like these episodes. Are there certain topics that you want to read about that are in the realm of this academic area between pathophysiology and pharmacology? Let us know. We want to hear from you. This is for you. If this is not up your alley, then we want to know so we can make that change.

Without further ado, let’s go ahead and get into the show.  

Signal Transduction

Signal transduction, what is it and why does it matter? I’m going to be the first to tell you that this is a topic that is difficult and I give David a lot of credit for tackling it because it’s complicated, but it also means that it’s probably not a topic that’s highly touched on a nursing school. Maybe it is, but maybe it’s in a very small way. It’s something that you should have an understanding of because it relates to how all drugs work in the body, as well as how all different components, like your endocrine system, work in your body as well. The cause-and-effect relationship between the causation and the effect that you want to achieve. That is why it’s important. To summarize it, signal transduction refers to how cells respond to external stimuli and convert them into intracellular signals.

External stimuli and how your body converts them into intracellular signals cause a reaction in the cell. Whenever I think of signal transduction, a lot of the end result has to do with releasing things like calcium or different chemical mediators, electrolytes of that nature, that cause a chain reaction depending on what system it’s in.

G-proteins are in a family of proteins that play a key role in signal transduction. They act as intermediaries between cell surfaces and the receptors and intracellular signaling pathways. They help the cell and between the extracellular and intracellular, they play that role of helping convert into action. For example, in the heart, G-proteins are involved in the regulation of heart rate and contractility.

Specifically, the G-Protein Coupled Receptors, which is abbreviated GPCR, and cardiac cells bind to hormones such as adrenaline and noradrenaline, which then activate G-proteins. The activation leads to the production of Cyclic AMP, also sometimes called CAMP, which in turn activates Protein Kinase A, which is also called PKA.

You are probably like, “My head is spinning already with all these abbreviations.” Take a deep breath. We do have a table with all these abbreviations to get more familiar with them. To backtrack a little bit to make sure you caught all that, the G-Protein Couple Receptors, the GPCRs and cardiac cells bind to hormones such as adrenaline and noradrenaline, which then activate G-proteins.

This activation leads to the production of Cyclic AMP, CAMP, which in turn activates Protein Kinase A, PKA. PKA then phosphorylates various target proteins in the heart, which leads to increased heart rate and contractility. If that painted any picture for you visually, it’s a chain reaction that has multiple steps to it.

This is how different receptors work in your body. It’s usually a multiple-step reaction. This is a process that you are going to have to learn in anesthesia school and something that you can learn now because it does relate to how drugs work in the body and how you get that cause and effect relationship. We are going to get into more detail on exactly how that is.

Let’s get into the arteries. G-proteins are involved in the regulation of vascular tone. G-proteins and vascular smooth muscle cells bind to hormones such as angiotensin-2 and endothelin-1. G-protein-coupled receptors, again in the vascular smooth muscle cells, bind to hormones such as angiotensin-2 and endothelin-1, which activate the G-protein. This activation leads to the production of something called inositol triphosphate or IP3, which in turn releases calcium from intracellular stores.

The release of the intracellular calcium leads to contraction of the smooth muscle cells and decreases arterial diameter, thereby increasing vascular resistance in the blood pressure. This causes vasoconstriction. We talked about how it increases contractility of the heart, how it increases the heart rate, and how it can increase your vasoconstriction or blood pressure.

Nerve Network

Signal Transduction: The release in intracellular calcium leads to contraction of the smooth muscle cells and decreases arterial diameter, thereby increasing vascular resistance in the blood pressure.

Start thinking about what drugs do these things because this is the process of that happening. Think about the vasopressors you use, which increase heart rate and blood pressure versus which only increase blood pressure. Start thinking about how these pathways will then differ based on which drugs those are.

Certain drugs can affect G-protein signaling in the heart and arteries. For example, beta blockers are drugs that block the G-protein-coupled receptor-mediated activation of the G-proteins, just in the heart leading to a decrease in heart rate and contractility. This makes beta-blockers effective in the treatment and conditions such as hypertension and heart failure.

Calcium channel blockers are another class of drug that affect G-protein signaling in the arteries by blocking the influx of intracellular calcium into the smooth muscle. This then leads to the relaxation of the smooth muscle in the cells, increasing arterial diameter and decreasing vascular resistance and blood pressure. It increases the diameter. I always think of arteries like a hose. That’s how I visualize it for myself.

If you are increasing the diameter, you are making the hose bigger, which is going to make the blood pressure lower and decrease vascular resistance. It’s going to decrease the blood pressure. You are going to have a bigger hose to move through. In summary, G-proteins are a crucial component of signal transduction pathways in the heart and arteries.

By understanding how they work and how certain drugs affect their signaling, we can better understand what treatment modalities affect cardiovascular conditions. One other example I want to share and something that is important as far as terminology goes- We talked a little bit about beta blockers and things of that nature. For example, stimulation of the beta-1 adrenergic receptor in the heart results in positive contractility, but it’s also called an inotropic effect.

Contractility is also known as a positive inotrope. Saying terms like positive inotrope versus increased contractility shows your understanding of the pathophysiology a little bit deeper than the surface-level contractility. Positive inotrope is a positive contractility if you think of it that way. Then you also have chronotropic effects, and chronotropic effects are where you increase your heart rate.

A positive chronotrope is something that increases your heart rate. A negative chronotrope would decrease your heart rate. The last key term that I want you to understand is dromotropic effect. The dromotropic effect simply increases a positive trope, increasing the rate of conduction through the AV node. It speeds up the process of signaling through the AV node. That’s a dromotrope. It takes it from one area in the heart to the other area in the heart much quicker. A negative dromotrope will then slow it down.

These are key terms that you should be using when you speak about certain drugs. This will come across in a very positive light in your interview and give you a better understanding as you enter your anesthesia training. Let’s review again. A positive inotrope means positive contractility. A positive chronotrope means a positive increase in your heart rate and a positive dromotrope effect means a positive increased rate of conduction through your AV node. If it was the negative effect, it would be the opposite. Whether you need to use arrows or different colors, red, green, and whatever works for your brain to keep those terms in the front of your brain, I encourage you to do so.

Vasopressors

Next, we are going to go into vasopressors since we briefly touched on that. Vasopressors are a class of drug that act on the cardiovascular system to increase blood pressure causing vasoconstriction, which is the narrowing of the blood vessels. Vasopressors can work through various mechanisms, including the effects on the G-proteins.

One main G-protein-coupled receptor involved in the regulation of blood pressure is the alpha-1 adrenergic receptor. A main G-protein-coupled receptor involved in the regulation of blood pressure is the alpha-1 adrenergic receptor. You have probably heard of that. That’s a G-protein-coupled receptor. This receptor is found on smooth muscle of cells and blood vessels and is activated by catecholamines such as adrenaline and noradrenaline, which are released by the sympathetic nervous system. When alpha-1 adrenergic receptors are activated, they signal through G-proteins to increase intracellular calcium.

I feel like calcium is a repeated theme. Is it not? Calcium is a very important electrolyte in our body. When levels of intracellular calcium increase, it leads to contraction in vasoconstriction. This mechanism allows vasopressors that target alpha-1 adrenergic receptors, such as phenylephrine, to increase blood pressure by constricting blood vessels.

Calcium is a very important electrolyte in our body. Click To Tweet

Phenylephrine is an alpha-1 adrenergic receptor type of drug. That’s one of the main ways and mechanism of action that phenylephrine works. If you dive even deeper, you are going to go into the G-protein-coupled receptor and how it releases calcium. This is how you take your knowledge and go deeper, which is the whole point of doing these academic sessions with you.

Another G-protein-coupled receptor involved in regulation of blood pressure is vasopressin of receptor. Vasopressin also known as an anti-diuretic hormone. It’s a peptide hormone that is released by the pituitary gland. That’s important. You should memorize that. I feel like that’s always on tests. In response to low blood pressure, you do release vasopressin or low blood volume.

If you have low blood pressure or low blood volume, your pituitary will then release the vasopressin receptor. Vasopressin acts on vasopressin receptors and blood vessels to because of vasoconstriction and increased blood pressure. Vasopressin is a receptor signal through G-proteins to increase intracellular calcium levels and activate various intracellular signaling pathways, ultimately leading to vasoconstriction.

G proteins play a very key role in signal transduction. They act as intermediaries between cell surfaces in their receptors and intracellular signaling pathways. Click To Tweet

Vasopressors that target vasopressor receptors, such as vasopressin, can increase blood pressure by causing vasoconstriction. A common pathway is the G-protein-coupled receptors. They interact with different receptors such as the alpha-adrenergic receptor and things of that nature. A lot of them tend to release calcium and calcium has effects both on your vascular system and your heart.

I hope this painted a brief overview. Now I’m going to let David take it away with his visual recording of this. He does talk it out, but if you are a visual learner, I highly encourage you to go over to the YouTube channel, which CRNA School Prep Academy and watch the video there. The notes also go over the video aspect of this with bullet points on the things that he talks about so you have a nice outlined way of following along.

G-Protein-Coupled Receptors

My name is David and we are talking about signal transduction. When you think of signal transduction, the first thing I want you to think of is the messenger system. It’s extremely important and it’s used all throughout the body. However, it’s a topic that many nurses don’t learn in nursing school. It is something that you will learn in CRNA school, but if you know it before your interview, it will set you so far apart from your competition. At the end of the day, you want to stand out from whoever is interviewing before or after you.

I like to start with the G-protein-coupled receptors and I have this list right here. I don’t want you to focus too much on knowing the names of these terms. For example, you probably should know that G-protein-coupled receptor is GPCR or something like that. For example, knowing that GDP is Guanosine-5-triphosphate. If you ever see a five like there, for example, and if you go down to PIP2, you will see there are 4 or 5 there and IP3. There are 1, 4, and 5.

Those are more things. The numbers are more for organic chemistry and structure and things of that nature, and it helps for if you are drawing them out and things like that in an organic chemistry class or something like that. Is that important for us? No. It’s something that I put in there because sometimes people put it in there. Sometimes they don’t. Is it important? No, but for your own little knowledge.

Some things on here we have adenylyl cyclase. That’s an enzyme. If anything ever ends with ase, it’s probably an enzyme. There are other terms on here that we are going to talk about. Sometimes I may call things CAMP or cyclic AMP whichever, but you can always relate back to this list that I have here of terms, and this will help.

When I talk about the G-protein-coupled receptor, then I’m going to draw right here and it’s on the plasma membrane and it weaves in and out of it seven times. Seven times is not super important. That’s not very critical, but it’s something interesting. Some little cool little information. Picture this little line. It’s leaving in and out membrane seven times. At the top of it, there’s this portion ligand or signal combine-2. On the bottom on the opposite side of that, you will have three little sub-units. We are going into detail on those, but just so you know, the G-protein receptor has three sub-units attached to it.

Close up photo of red blood cells in the body

Signal Transduction: The G protein-coupled receptor is on the plasma membrane and it weaves in and out of it seven times.

We are going to draw it out a little bigger here for us and draw this G-protein-coupled receptor and I’m going to use different colors here so that we can go off this. We will call this first sub-unit gamma. We will call the second one alpha, and then we will call this one beta. Once a signal or ligand attaches to the G-protein-coupled receptor and in essence turns it on, you will have this confirmational change that will occur with these three sub-units.

What basically happens is that the beta and gamma sub-units will end up staying at the top near the plasma membrane. I will draw an arrow to show that we are undergoing this confirmational change and basically redraw the G-protein-coupled receptor. You will see that the gamma sub-unit will stay up top of the plasma membrane and the beta will as well too, but the alpha sub-unit pops off.

On that alpha sub-unit, the GDP will be able to convert into GTP, and then you have a GTP found alpha sub-unit and it’s activated. It is ready to go. This is some advanced stuff. ]Now that we have this activated alpha sub-unit, we can get into some of the pathways that the G-protein receptors can take the essence.

The first one is called a GS pathway and the S stands for stimulatory. You can even write that if you want. That’s the first pathway. That will be on the left. On the right, we will write G inhibitory and then all the way on the right, we will write GQ. You may be thinking, “We have a GS and GI, but what does the GQ stand for?” A little history lesson. It’s not that important that you know this, but the Q doesn’t stand for anything.

Back in the day, when they discovered it, they were trying to figure out a letter that they could use. The earlier letters in the alphabet were already taken. They were like, “Let’s put GQ.” That’s how that ended up going. Now that we have this GS pathway, the G stimulatory pathway. When the alpha sub-unit, and remember it has GTP bound to it, and it’s activated. What happens is all the sub-unit, if we are going the G stimulatory pathway, it can activate something called adenylyl cyclase. What does adenylyl cyclase do? Adenylyl cyclase will end up taking ATP and turns it into cyclic AMP. Let’s say that we are activating or we are doing something or producing it that way.

Cyclic AMP can go and activate something called Protein Kinase A or PKA, and PKA will go on and do other things and we will talk about that in other episodes. PKA is very important in some instances because it will help with calcium and other parts of cells and things like that to be able to cause contractions, or you will also see it with vasoconstriction. That is the GQ.

Red blood cells

Signal Transduction: PKA is very important in some instances since it will help with calcium and other parts of cells and things like that to be able to cause contractions.

I like to think that PKA, whenever I think about that, I think more the heart for the GS pathway. That’s the first thing that of. I will get to that in another episode. Do not fret. G inhibitory pathway, the one right in the middle. We do not activate adenylyl cyclase. It inhibits because it’s inhibitory. Two red arrows with a line through it because we are not activating adenylyl cyclase.

What does that mean? We do not have ATP going and becoming cyclic AMP. That’s not happening. We therefore do not get PKA. G inhibitory, where do you see that? You can see in the heart. The parasympathetic does as well too. We are going to get to that, but that’s the one that I think about when I think about the parasympathetic nervous system working on the heart.

Now, the GQ pathway. The GQ pathway, when the other sub-unit activates that, does not use an adenylyl cyclase. It uses something called phospholipase C. Once phospholipase C is activated, it converts into IP3 and DAG. Why is that important? IP3 will go and cause calcium to be released from the SR or the Sarcoplasmic reticulum.

That is important. DAG will go on. DAG activates something called protein kinase C, and that is important too. When you think GQ, I want you to think about your arteries. That’s the first thing that I think about. There is another thing we will get into later that comes from the GQ called a Rho-kinase pathway.

If you are into it and you want to look it up and you want to look into things, just know that there is a Rho-kinase pathway. We will get into that. You will see that it inhibits myosin light chain phosphatase. That’s not important right now, but if you are somebody who looks ahead, don’t fret over that. I will get into that. If you are not, don’t even worry about it. We will get into that. The GQ, I want you to think arteries.

The take-home message for this is that you have a G-protein-coupled receptor that will either activate or inhibit PKA. You have a G-protein receptor that will get you calcium and PKC activation. That’s a take-home message. These are important for whenever you give a medication, whenever you think about endocrinology.

In endocrinology specifically, you have vasopressin. Vasopressin, specifically the V2 receptor and glucagon, both work on the GS pathway. I’m going to write that down here. Vasopressin, V2 receptor, and glucagon, those work G stimulatory. GQ, you have vasopressin again, but as you probably guessed it, it’s the V1 receptor. You also have angiotensin to the GQ pathway. I’m not that familiar with angiotensin-2 as far as the medication. I have heard that there are some places that do use it as a medication. It’s like a pressor. I don’t know. My place never did that. Props, if you use it, cool. If not, don’t fret.

Other medications that you can use in the G stimulatory that come to mind are norepinephrine and epinephrine. These norepinephrine and epinephrine will use G stimulatory in the heart. The blood vessels example like I ask people all time to talk about norepinephrine and how it works in mock interviews. That’s what I do. Norepinephrine will also talk about in the arteries. It also works in the arteries, but it’s the GQ pathway. You stand out in interviews and support when you are in CRNA School as well, because you will be learning this and this is something that you need to know.

That wraps it up. Thank you so much for tuning in and I hope you found that helpful. I would love to hear from you. Don’t forget. You can go ahead and send us an email at Hello@CRNASchoolPrepAcademy.com to let us know what you thought. Be sure to grab your study notes. Just so you know, this is part 1 of at least a 2-part series, so we may break it up even into a part 3 series depending on the length of the part 2. There are more concepts to come around this topic. Stay tuned and thank you so very much for tuning in. I appreciate you. We will see you next episode. Cheers to your future.

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