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Pacemaker current

From Wikipedia, the free encyclopedia

The pacemaker current (If, or IKf, also called funny current) is an electric current in the heart that flows through the HCN channel or pacemaker channel. Such channels are important parts of the electrical conduction system of the heart and form a component of the natural pacemaker.

First described in the late 1970s in Purkinje fibers and sinoatrial myocytes, the cardiac pacemaker "funny" (If) current has been extensively characterized and its role in cardiac pacemaking has been investigated.[1][2][3] Among the unusual features which justified the name "funny" are mixed Na+ and K+ permeability, activation on hyperpolarization, and very slow kinetics.[1]

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Transcription

So we're going to talk about pacemaker cells. And these are actually really, really cool cells, because these are the cells in our heart that basically keep all of the heart beating, both in a certain rhythm, and at a certain pace. So these cells are going to work from the moment that you're conceived, in a little fetus in the womb, all the way to the point where you die. These pacemaker cells have a property, and we call that property automaticity. Actually, it has the word automatic right in there, right. So, automatic, and all that means is that you don't actually need a neighboring cell to tell this guy that he needs to fire an action potential. Pacemaker cells can do it themselves. It is actually a pretty neat thing, and, when you think about it, these are the cells where everything really begins then. So there's three clumps of pacemaker cells, or three groups that we talk about. One would be the group of cells sitting in what we call the sinoatrial node, SA node, and this is probably the most common group that we think of. But there's also some pacemaker cells in the atrioventricular node, or AV node, so this is another group of potential pacemaker cells. And finally, there is a third group in what we call the bundle of His and Purkinje fibers. Now I know this sounds like I'm speaking a new language because I'm throwing out a lot of words that really may not make a lot of sense, but all that you need to know about these three are that they are just in different parts of the electrical conduction system of the heart. So they're all parts of the electrical conduction system and they're just at different locations in the heart. They make up part of the electrical conduction system, and they are all given this special property of having the ability to pace the heart. Let me make a little bit of space now. To really understand these three groups of cells and the kind of magic they can actually bestow upon us, let's talk in terms of how heart cells really talk and think. And they don't really think the way you and I might think. They think in terms of voltage. This is their language. And so to understand them, let's use it. So this is millivolts, and let's say this is positive, and let's say this is negative, because that's probably the most intuitive. We have a few ions that are going to pass into and out of cells, and you know that ions are going to help determine the voltage of a cell, and we've talked about that in other videos. And so let's say this is calcium right here. This is calcium. So why am I drawing an arrow with a voltage up there? 123-- what that means is that if calcium was the only ion moving into and out of a cell, then the cell's voltage would be 123. So it really just tells you what would happen if that was the only ion that had the ability to permeate a cell. Now let's say sodium was the only ion able to permeate a cell, going into and out of a cell. Then the membrane potential would be 67. So it would actually be almost a little bit more than half. And then, finally, if, let's say, potassium was the only ion that could get into and out of a cell-- this is potassium down here-- then the membrane potential would be negative 92. So potassium likes things to be more negative. Now in real life you would have cells-- and I'll draw a cell right here-- that actually are permeable to multiple things, right? They're not just permeable to one ion. And let's say, for argument's sake, that it's half-permeable to calcium and half-permeable to sodium. Well if it's exactly half and half, then your membrane potential would be somewhere in the middle, somewhere like there, and that works out to about-- What is that? Let's see if I can do my math quickly. 97 or so. So around 97, maybe 96. So that would be about 96 millivolts, because it would be half and half. So it would be split between the two. Now let's say that it was 99% permeable to potassium and 1% permeable to sodium. Well then it would be down here, very, very close to potassium. It would probably be negative 91, so depending on how permeable it is to what ion, you can kind of predict roughly what the membrane potential is going to be. Now let's start out-- let's say that our cell here is going to be one of these pacemaker cells, and it's permeable to just salt. Actually, you know what. Before I do that, let me tell you what its voltage is. Let's say its voltage is negative 60. I won't tell you how I got there. We'll figure that out later. But it's negative 60, and I tell you that it's permeable to just salt, or maybe not just salt, but predominantly salt. And we know salt is going to want to rush into the cell, because there's a lot more salt on the outside than on the inside. Now if that was the case, if it was at negative 60-- and put aside the thought of how did it get there in the first place. But let's say it was there. What would happen if it was permeable to primarily salt? Well it's going to want to eventually get up here, right? It might take some time, which is why I drew it all the way out there. And remember, this is our time access. It might take some time to get there, but it will eventually want to get there. It will eventually want to get over to, close to positive 67, if sodium is the major ion that it's permeable to. So it's going to start in that direction and, actually, that's about exactly what happens. It starts marching towards that point. Now it gets a little bit further along, from negative 60, so it's, like let's say negative 40, and then an interesting thing happens. It doesn't just continue to that purple dot. Let me erase that purple dot now. It doesn't continue there, but it actually hits a threshold. Now when I say threshold, you'll see in just a few moments what I mean. But it hits this threshold, and this threshold is for a new type of ion. So let me actually switch it up. I'm going to actually save myself some time by just cutting and pasting this, like that. I'm going to move it over here. So this is my cell, right? And now I got to negative 40 and a new channel emerges. So we have this channel here for calcium, and we have a bunch of them. So calcium starts dumping into the cell, and calcium, just like sodium, loves to be inside of the cell. Now you've got a lot of calcium, and what opened up these channels-- These are actually voltage-gated channels. That's actually why I said that there was a threshold. Because these channels-- I didn't actually draw them before-- they're there. It's not as if the cell just made these channels out of thin air. They were there the whole time, but they were closed, literally gated shut, and so now that you hit negative 40, that's their ticket. Now they open up, and they let all the calcium in. So that's why we call it voltage-gated, and that's why we say that there's a threshold. This is the word threshold. It really is talking about what is the voltage needed to open those calcium gates. So now calcium pours in. So now you can step back and think about what will happen to our white line. If calcium is the major ion that this cell is permeable to now-- I mean, it's still a little bit permeable to salt. You can see that-- but mostly calcium. It's going to want to rise up to calcium's resting potential, which is even higher than sodium's. So instead of chugging along slowly, it's going to start moving up in a nice steady clip. Now it's going to go up nice and quick, right? So it's going to start getting more steep. It was going slowly, and now it's going more steep, and it gets to, let's say, positive 10. And now the next interesting thing happens. So we said that these calcium channels are voltage-gated, and that's what makes them open. The cool thing is that, that's not only what makes them open. It's also what makes them shut. Let me actually draw this one more time. I'll just cut and paste it, and now I'll put it over here. And if that's what makes them shut, then watch what happens now. I'm going to actually erase this calcium, because now these voltage-gated channels are going to close down, and we're going to have to show them closed. So let's draw little x's here so no more calcium can get in. So you've got just that sodium and at the same moment that the calcium-gated channels close-- that same moment-- the potassium voltage-gated channels open. Now you have some potassium channels here that open up, and the potassium is going to escape, right? It's going to leave because potassium loves to leave the cell. It likes to get outside because that's the direction of its concentration gradient, and so, just like we said that the calcium has voltage-gated, so does the potassium. So these are voltage-gated as well, and they're voltage-gated to open when it's a little bit more positive. And, just like I said earlier that these voltage-gated channels exist, they certainly exist. I just didn't draw them. But they're closed. So they were closed up until this point. They were there the whole time. They were there in both scenarios, right there or there, and they just stayed shut. So if the potassium is escaping, what happens to our white line? Think about that. It's going to go towards, now that potassium is the dominant ion. Always think in terms of what's the dominant ion in terms of permeability. Our cell is mostly permeable to potassium right now, so the membrane potential is going to go towards potassium, and potassium is way down here. So it's going to start going down. So the membrane potential starts creeping down, creeping down, creeping down, and stops, stops right here, negative 60. Well, why did it stop? Why didn't it just go all the way down closer to negative 92? Just as the calcium-gated channels shut, so do the potassium. So these ones actually shut down as well. And I'm just going to erase this potassium at this point, because now they're shut, and I'm even going to put little x's through them. So basically these are not open for business, closed for business. So now we have just the sodium entering. Well this looks a lot like how we started, right? And so what happens is that this process repeats itself. It basically will just rise up until threshold. The calcium-gated channels slip up and open. Then they close. The potassium-gated channels open and they close, and we're back to just sodium. So this is how we get our action potential. This is how it forms, and you can see that. I didn't talk about any other cells. This is a cell doing it all by itself. And because the channels are constantly opening and closing, we don't really ever think of this cell as having a resting potential. It has a membrane potential, but it's never really resting anywhere. It's always on the move, right? It is always either rising or falling. So now if my heart rate-- let's say my heart rate is 60 beats a minute, right? 60 beats per minute, then what that means is that this right here-- this is one heartbeat. One heartbeat is happening in one second, right? Which I think is pretty sweet. All of this stuff is happening in one second. The sodium is coming in. Then the calcium is coming in, and then that stops, but then the potassium rushes out, and then that stops. And then the whole thing happens again and again and again, every single second. So this is how our heart is beating. This little cycle keeps going on and on and on. People will actually talk about different phases of this. There are obviously three basic phases that I've drawn out for us. So there's this phase 4. This is called phase 0, and this is phase 3. Now you're thinking, wait a second. This sounds totally wacky. Why would you call it phase 4, 0, 3? What sense does that make? And I'll draw for you an example of how the heart muscle-- actually the action potentials in the heart muscle --look, and you'll see how this naming system came about. I'm not trying to defend it, because I don't think it's the best, but this is at least how it came about. So when heart muscle beats, it looks like that. It doesn't look the way that we've drawn this one, and I'll get into that one some other time. But that's what it looks like, and if you were to number the different parts, the numbers would be basically-- This down here is phase 4. This is phase 0. Then there's phase 1, 2, and then 3. And so if someone kind of stepped back and took a look at this and said, well this phase 4 looks a lot like this guy, and this phase 0, this upward swing looks like this upward swing, and then this downward swing looks like this. So that's how the phase 4, 0, and 3 come about. And they said, well, I guess these pacemaker cells-- they don't have phase 1 and 2, so let's just ignore those two numbers. So that's why those two numbers are not included when I number 4, 0, and 3. But there is something actually kind of important I want to point out when comparing the phase 0 here. So in the pacemaker cell, the phase 0, right here-- it might seem pretty fast to you and I. It happens, let's say, in 1/10 of a second or in about 2/10 of a second, but, in fact, it's actually a little bit slower. Let me write it right here. It's actually a little bit slower than what happens with the heart muscle. This one is actually faster. I'm talking specifically about phase 0. So because it's slower, and that phase 0 is called the action potential, this is a slower action potential, and the other one is considered a faster action potential. So sometimes you might hear that term, the slow action potential cells, or something like that, and they're referring to the pacemaker cells when they say that. The last thing I should probably mention is that any time you go up like this, and you actually become less negative, that's called depolarization. I want to make sure that's really, really clear. So any time you become less negative, that's considered depolarization, and any time you become more negative, like that, that's considered repolarization. So in this case we have phase 4 and 0 are kind of slowly depolarizing, and then phase 3 is repolarizing our cell.

Function

The funny current is highly expressed in spontaneously active cardiac regions, such as the sinoatrial node (SAN, the natural pacemaker region), the atrioventricular node (AVN) and the Purkinje fibres of conduction tissue. The funny current is a mixed sodium–potassium current that activates upon hyperpolarization at voltages in the diastolic range (normally from −60/−70 mV to −40 mV). When, at the end of a sinoatrial action potential, the membrane repolarizes below the If threshold (about −40/−50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD); by this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, and thus the cardiac rate. The reversal potential of the funny current lies between -20 and -10 mV. [4]

Another unusual feature of If is its dual activation by voltage and by cyclic nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind directly to f-channels and increase their open probability.[5] cAMP dependence is a particularly relevant physiological property, since it underlies the If-dependent autonomic regulation of heart rate. Sympathetic stimulation raises the level of cAMP-molecules which bind to f-channels and shift the If activation range to more positive voltages; this mechanism leads to an increase of the current at diastolic voltages and therefore to an increase of the steepness of DD and heart rate acceleration.

Parasympathetic stimulation (which acts to increase probability of potassium channels opening but decreases the probability of calcium channel opening) decreases the heart rate by the opposite action, that is by shifting the If activation curve towards more negative voltages. When vagally-released acetylcholine (ACh) binds to muscarinic M2 receptors, this promotes dissociation of βγ subunit complexes, leading to direct opening of the G-protein–gated inwardly rectifying K+ channel (Girk/Kir) IKACh.[6]

Related currents

A similar current, termed Ih (hyperpolarization-activated), has also been described in different types of neurons, where it has a variety of functions, including the contribution to control of rhythmic firing, regulation of neuronal excitability, sensory transduction, synaptic plasticity and more.[7]

Molecular determinants

The molecular determinants of the pacemaker current belong to the HCN channel (hyperpolarization-activated cyclic nucleotide–gated channel), of which 4 isoforms (HCN1 to HCN4) are known. Based on their sequence, HCN channels are classified as members of the superfamily of voltage-gated K+ (Kv) and CNG channels.[3][8]

Clinical significance

Ivabradine

Because of their relevance to generation of pacemaker activity and modulation of spontaneous frequency, f-channels are natural targets of drugs aimed to pharmacologically control heart rate. Several agents called "heart rate reducing agents" act by specifically inhibiting f-channel function.[3] Ivabradine is the most specific and selective If inhibitor and the only member of this family that is now marketed for pharmacological treatment of chronic stable angina in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. Recent studies have also indicated that funny channel inhibition can be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients with heart rate ≥70 bpm.[9]

Cardiovascular diseases represent a major cause of worldwide mortality, and the relevance of the genetic component in these diseases has recently become more apparent. Genetic alterations of HCN4 channels (the molecular correlate of sinoatrial f-channels) coupled to rhythm disturbances have been reported in humans. For example, an inherited mutation of a highly conserved residue in the CNBD of the HCN4 protein (S672R) is associated with inherited sinus bradycardia.[10] In vitro studies indicate that the S672R mutation causes a hyperpolarizing shift of the HCN4 channel open probability curve of about 5 mV in heterozygosis, an effect similar to the hyperpolarizing shift caused by parasympathetic stimulation and able to explain a reduction of inward current during diastole and the resulting slower spontaneous rate.[citation needed]

Biological pacemakers, generally intended as cell substrates able to induce spontaneous activity in silent tissue, represent a potential tool to overcome the limitations of electronic pacemakers. One of the strategies used to generate biological pacemakers involves the use of cells inherently expressing or engineered to express funny channels. Different types of stem cells can be used for this purpose.[8]

See also

References

  1. ^ a b Brown HF, DiFrancesco D, Noble SJ (July 1979). "How does adrenaline accelerate the heart?". Nature. 280 (5719): 235–6. Bibcode:1979Natur.280..235B. doi:10.1038/280235a0. PMID 450140. S2CID 4350616.
  2. ^ DiFrancesco D, Ojeda C (November 1980). "Properties of the current if in the sino-atrial node of the rabbit compared with those of the current iK, in Purkinje fibres". The Journal of Physiology. 308: 353–67. doi:10.1113/jphysiol.1980.sp013475. PMC 1274552. PMID 6262501.
  3. ^ a b c Baruscotti M, Bucchi A, Difrancesco D (July 2005). "Physiology and pharmacology of the cardiac pacemaker ("funny") current". Pharmacology & Therapeutics. 107 (1): 59–79. doi:10.1016/j.pharmthera.2005.01.005. PMID 15963351.
  4. ^ DiFrancesco, Dario (19 February 2010). "The Role of the Funny Current in Pacemaker Activity". Circulation Research. 106 (3): 434–446. doi:10.1161/CIRCRESAHA.109.208041. Retrieved 6 September 2023.
  5. ^ DiFrancesco D, Tortora P (May 1991). "Direct activation of cardiac pacemaker channels by intracellular cyclic AMP". Nature. 351 (6322): 145–7. Bibcode:1991Natur.351..145D. doi:10.1038/351145a0. PMID 1709448. S2CID 4326191.
  6. ^ Mesirca P, Marger L, Toyoda F, Rizzetto R, Audoubert M, Dubel S, Torrente AG, Difrancesco ML, Muller JC, Leoni AL, Couette B, Nargeot J, Clapham DE, Wickman K, Mangoni ME (August 2013). "The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation" (PDF). The Journal of General Physiology. 142 (2): 113–26. doi:10.1085/jgp.201310996. PMC 3727310. PMID 23858001.
  7. ^ DiFrancesco JC, DiFrancesco D (2015). "Dysfunctional HCN ion channels in neurological diseases". Frontiers in Cellular Neuroscience. 6: 174. doi:10.3389/fncel.2015.00071. PMC 4354400. PMID 25805968.
  8. ^ a b Barbuti A, Baruscotti M, DiFrancesco D (March 2007). "The pacemaker current: from basics to the clinics". Journal of Cardiovascular Electrophysiology. 18 (3): 342–7. doi:10.1111/j.1540-8167.2006.00736.x. PMID 17284289. S2CID 18907313.
  9. ^ Fox K, Ford I, Steg PG, Tendera M, Ferrari R (September 2008). "Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial". Lancet. 372 (9641): 807–16. doi:10.1016/S0140-6736(08)61170-8. PMID 18757088. S2CID 26282333.
  10. ^ Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D (January 2006). "Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel". The New England Journal of Medicine. 354 (2): 151–7. doi:10.1056/NEJMoa052475. PMID 16407510.
This page was last edited on 8 November 2023, at 21:33
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