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Action potential and Na+

  1. Aug 1, 2008 #1


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    Hi All,

    It is a fact that Na+ ions cross the membrane and enter the cell during the rising phase of the action potential. The process happens because Na ions channels are open.
    Then the ions channels becomes inactivated/closed for a while.

    What happens to the Na+ ions that entered the cell?
  2. jcsd
  3. Aug 1, 2008 #2
    The sodium ions stay there for the time being until they are actively pumped back out of the cell by the Na/K ATPase pump.

    What happens during an action potential is sodium atoms briefly flood into the cell down their concentration gradient which makes the inside of the cell a bit more positive than normal. To restore the membrane potential back to normal, potassium channels are opened shortly after the sodium ion channels are opened and potassium flows out of the cell down its concentration gradient (carrying its positive charge with it, hence putting the inside of the cell back to its original negative state after it leaves). The sodium is then pumped out, and the potassium is pumped back in using the ATP dependent pumps which completes the cycle.
  4. Aug 1, 2008 #3


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    This explanation contradicts twice the facts:
    1. Na K pumps are not involved in AP and it is a slow process.
    2. The graph doesn't lie, the decay is also... fast.
  5. Aug 1, 2008 #4

    Andy Resnick

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    Lots of things happen during an action potential- a transient regenerative spike in the resting membrane potential that changes from around - 60 mV to +20 mV. Some ion channels cause the spike, some channels respond to the spike.

    The resting potential is caused by a concentration imbalance between sodium (high outside, low inside) and potassium (low outside, high inside) and is maintained by the Na-K ATPase combined with a potassium channel.

    The action potential is caused by changes to the sdium and potassium conductance, leading to a small influx of sodium and efflux of potassium, corresponding to depolarization. It's important to note that small Na and K ion currents are sufficient to cause large changes in the membrane potential.

    The channels that allow depolarization and repolarization are voltage-gated ion channels- channels do not use ATP to move ions, but allow passive diffusion of ions through the membrane as a function of the membrane potential. Hodgkin and Huxley,in 1952 using squid axons, generated a model system demonstrating how an action potential is generated by having voltage-gated changes to ion conductance.

    Briefly, the rapid increase in sodium conductance causes the depolarizing phase as sodium influxes. Opposing this is hyperpolarizing potassium (and chloride) channels, which must be overcome in order to initiate an action potential. The delayed potassium conductance change is what brings about repolarization. Potassium channels determine the resting potential and terminate the action potential.

    So the big picture is that the action potential is caused by movements of small numbers of sodium and potassium via ion channels.

    Calcium channels are also involved, as they are also voltage-gated, and play a role in muscle contraction. There, the calcium influx causes calcium-mediated calcium release from the sarcomplasmic reticulum, which is then pumped back in by the SERCA pump.
  6. Aug 1, 2008 #5


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    I fully accept this explanation but if the rising is done by an influx then the decay must be done the same way in opposite direction (efflux) but all papers speak about Na ions channels inactivated or closed.
    How is it possible to get a rapid decay when gates are closed?
  7. Aug 1, 2008 #6

    Andy Resnick

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    Not all the papers. Have you read the original Hodgkin-Huxley papers? Potassium channels are a key player.

    There are a few concepts required to understand what is going in:

    1) reversal potential. This is the potential at which no ions flow through the channel.

    2) Voltage dependence of the open probability. This is what is meant by voltage-gating

    3) Inactivation of a channel. I don't fully understand this, but it means the channel is open but does not conduct ions.

    4) channels can be rectifying channels- ions are allowed to move in one direction only.

    The reversal potential of outwardly rectifying potassium channels (Shaker-type) is about -80 mV. The reversal potential of sodium channels is around + 50mV. The 50% open probability for K+ channels is around -30 mV, that for Na+ channels around -50 mV. The ~ 0% open probability is about -50 and -70 mV, respectively and the ~100% open probability is about -10 and -30 mV, respectively.

    The voltage-gated Na+ channels produce the initial depolarization (ignore Ca+ for now). Shaker-type K+ channels are outwardly rectifying and also *delayed* in opening, and is responsible for repolarization. Now remember, the action potential is generated by changes in the *conductance* of a channel, meaning the open probability. The actual currents are quite small. The K+ channels, because of the low reversal potential, act to oppose the Na+ channel and maintain the resting state.

    Again recall that small numbers of ions moving across the membrane will produce large changes in membrane potential: 0.004% of the K+ in a cell moving across the membrane will produce a potential of -61.5 mV.
  8. Aug 1, 2008 #7

    Perhaps the confusion here is caused by my sloppiness so let me clarify one point; the reinstatement of the Na/K gradients via the Na/K pump is NOT part of the action potential (as you mention). This part of the process happens after the fact.

    The influx of Na accounts for the change in membrane potential and the efflux of K accounts for the restoration of the original membrane potential (as described in satisfying detail by Mr. Resnick in his posts above). I was including the Na/K pump as part of the description only to give the full picture of how the cycle works.
  9. Aug 1, 2008 #8

    Andy Resnick

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    I've never seen a reasonable discussion of Cl- transport in all this stuff: most of what I've read is that Cl- merely maintains cell volume (via osmotic balance). What's your presepective?
  10. Aug 1, 2008 #9
    From my understanding the Cl ion channel is somewhat of an oddity which is why it often gets completely bypassed in these discussions (it is sort of like that weird half brother that nobody likes to talk about...), but it does serve a purpose in the above process in that it can protect against overly negative membrane potentials (such as if too much potassium leaves the cell during the efflux after an action potential).

    As with the sodium and calcium ions, Chloride ion is kept at a higher concentration outside the cell than that of chlorine ion inside the cell. But unlike the previous two ions, when the gate for this channel is open, chlorine ion moves spontaneously *against* its concentration gradient and even more chlorine flows out of the cell (it is for this reason that I believe it is usually ignored...its easier to ignore this behavior than it is to try and explain it, but I will do my best below ^^).

    The only time this sort of thing can happen is when the membrane potential (Vm) is more negative than the normal desired amount (and my guess is the chlorine channel is not even opened unless triggered by this overly negative potential although I have yet to see this hunch "officially" confirmed). To see how this can happen, the formula that describes the Gibbs free energy criterion (or change in Gibbs, dG) for all of the above mentioned ion channel processes (borrowed from the text "Principles of Biochemistry" by Nelson, Cox) is:

    dG = RTln(Cin/Cout) + ZF(Vm)

    The logarithmic term in this equation describes the effect of concentration on membrane transport for ions. If the concentration on the inside (Cin) is lower than (Cout), as it is for sodium, calcium, and chlorine, then "RT ln (Cin/Cout)" as a whole will always be negative and ions will move spontaneously from a higher concentration outside to a lower concentration inside. However, this is not the only factor...the right term ZF(Vm) also determines the direction of ion flow. For chlorine, Z = -1....so in this case, if Vm is also large and negative then "ZF(Vm)" as a whole can be positive. If this term is positive and larger than the logarithmic term, then the movement will be against the concentration gradient and even more chlorine ion will move out as the Gibbs moves towards zero for the overall process.

    This is how the chlorine ion channel works. The effect is much the same as the sodium and calcium channels (it makes the inside of the cell less negative). However, it does so by removing the negatively charged chlorine ions until Vm reaches the proper resting potential.

    So then, the question might be "why bother with the chlorine ion channel? If the membrane becomes too negative, why not just let in more sodium and calcium to make things positive and normal again?" Well, it makes sense to do it this way as both sodium and calcium channels are directly part of the signal transduction process (as opposed to the potassium and chlorine channels which to the best of my knowledge merely transfer ions and not signals). Letting more of either sodium or calcium ions flow in could affect the membrane potential signal sent from these channels in a negative way (or have some other damaging effect such as creating unwanted additional signals to be propagated). In contrast, there is no action potential generated at the Chlorine ion channels, and so this channel allows the membrane potential inside the cell to become more positive without affecting the signal transduction process at all.

    Or at least, that is my understanding of this at the present. Of all of the ion channels mentioned in this thread, the chlorine channel is by far the least studied of the bunch and may also serve some additional purpose that I am neglecting...
    Last edited: Aug 1, 2008
  11. Aug 2, 2008 #10


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  12. Aug 2, 2008 #11
    Yeah Soma, we know these things (no need to bold!)...that's why I wrote in my post above:

    The problem is that your original question about what happens to sodium cannot be answered without considering what happens a short (very short) while *after* the signal has been sent.

    I know the process as a whole is somewhat confusing, and I also know many Cell Bio texts (including the one that I read a few years ago) ONLY mention the sodium and calcium channels when talking about signal transduction and ignore discussion of the "cleanup" process involving the potassium and chlorine channels altogether (or they put the description of these channels in a completely different place)...my guess is this probably lies at the root of your original question about what happens to sodium after the action potential?

    For a more complete view of the process that integrates the roles of the various channels into one discussion, I suggest having a look at the description given in the above mentioned "Lehningers Principles of Biochemistry" by Nelson, Cox (4th or I guess now 5th ed.) as it gives what I consider to be the most clear description of the interplay between all these channels that I have seen in a text (or at least it has a really good graphic of the ion channels, see Chapter 12).
  13. Aug 3, 2008 #12


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    the K conductance is lower than the Na one and the number of K channel is 10 time lower than the Na one.
    How is it possible that in quite the same time (because you excluded all other ions species) the voltage decays like it grew...quickly (but Na ions are confined inside and Na channels closed or inactive)?
  14. Aug 3, 2008 #13


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    The delay makes trouble in a fast decay. :smile:
  15. Aug 4, 2008 #14


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    I ordered the book.
  16. Aug 4, 2008 #15
    Somasimple seems to have some kind of axe to grind against the Hodgkin-Huxley theory of how action potentials are generated from electrochemical gradients and propagated down an axon.

    Here is a previous thread on physicsforums where we discused this similarly: https://www.physicsforums.com/showthread.php?t=182840

    If you google somasimple and action potential you will find many hits with him talking about the same things on many forums. As I recall when I looked him up last time, he had a long discussion about this on a wikipeda talk page as well.
  17. Aug 4, 2008 #16

    Andy Resnick

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    Nice post- it took me a while to work through the whole thing.

    My understanding (which appears to be similar to your explanation) is that movement of sodium or potassium changes the membrane potential not by adjustments to the concentration, but by movement of charge- that way small numbers of ions have a large effect on the membrane potential. Conversely, calcium movement does operate by concentration, because the intracellular Ca++ concentration is so low.

    Chloride is intermediate- as you point out, the concentration gradient is small, so ions can flow either way depending on the details of the membrane potential. Plus, paracellular transport of Cl- is usually invoked to "complete the circuit" and maintain overall charge neutrality. So, just as the rule of thumb is that "water follows sodium", I guess "chloride follows charge".

    I mostly work on the kidney- in the renal tubule, specifically the juxtaglomerular apparatus, Cl- is the rate-limiting ion for the Na/K/Cl cotransporter, which translates into a cell volume trigger back to the glomerulus: Increasing chloride concentration leads to a decrease in the glomerular filtration rate as a feedback mechanism for salt and water homeostasis.

    Also, Cystic Fibrosis is purely a defect of cloride transport (CFTR). One hypothesis is that defective chloride transport leads to excessive and unregulated sodium absorption- it's not clear to me if the Cl- is absorbed or excreted- but the result is the same: dehydrated mucus, leading to problems in the lung and digestive system.
  18. Aug 4, 2008 #17
    It is in the spirit of science to question things. My take is that so long as nobody kills or harms each other over differences in ideas then I see disagreement as a very very good thing (in fact, it is the horrible necessity of progress). Of course, people DO kill and harm each other over differences in opinion...so *ahem ahem*, in light of that observation, 95% of the time when I encounter someone with a different opinion, my response is to simply keep my ideas to myself. You would be amazed at how many times I have typed out these long posts here on PF only to delete them before posting, because I did not want to risk my ideas provoking a negative response in the person on the other end...

    You will not be disappointed. I haven't had a chance to really look at the 5th edition yet, but the 4th did a better job on the cell bio topics than pretty much every other dedicated cell bio text that I have seen.

    As for the role of chloride in osmotic processes, I am sure all these ions and their individual concentrations have to be very carefully regulated to ensure proper balance. As far as signal transduction processes go, I don't see osmotic balance as too much of an issue per say, because of the rapid way with which the concentration gradients are manipulated and restored to balance, and the small size of the concentration changes with respect to the cytosol as a whole. Certainly in the case of a defective ion channel (such as in CF) where balance cannot be restored properly and the mistake "piles up" over time, the importance of establishing osmotic balance for these channels becomes readily apparent.

    As far as the movement of charge itself being the dominating force (at least for external plasma membrane ion channels) as opposed to concentration, everything I have read lately points to that idea being right on. In my understanding, the 2nd term of that above equation dealing with the impact of charge on the process is THE critical contributor to the functioning of the voltage gated ion channels that appear on the external plasma membrane (intracellular channels such as the calcium channel in the ER lack a strong membrane potential and can be an exception, which I will get to in a minute). This is further reinforced when you consider that chloride is generally NOT kept with a small concentration gradient (yes, one of the many puzzling things about it); in fact, in most cases the concentration gradient is the same for chloride as it is for sodium. For example, in squid axon sodium is 440 mM outside and 50 mM inside whereas chloride is at 560 mM outside and 40-150mM inside. Yet, it is known that at least in neurons, chloride moves against the concentration gradient in its ion channels. My thinking is that the concentration gradients are set up to create, maintain, and tweak the membrane potential while the rapid changes in the membrane potential itself (created by opening or closing channels a bit too long compared with the norm) control the actual movement of ions and initiate the main responses (this is sort of clouded by the fact that sodium has *both* an inward concentration gradient and an inward electrochemical gradient for it that together "push" sodium into the cell when its channel opens, prompting explanations to focus on either one or the other).

    Indeed the sensitive membrane potential, and not concentration, now seems to be the main driving force for the proton channels used in the production of ATP, at least for eukaryotes (plants do seem to use the "old pH model" that gets taught in schools which I won't get into here). This became apparent once they found out that the eukaryotic membrane wasn't "hording" protons in a little comparment like it does for intracellular calcium or in plants, but that hydrogen ions were free to diffuse away from the plasma membrane and become diluted throughout the cytosol. It is like dropping a bottle of concentrated hydrochloric acid into the ocean (which I should mention here is something that nobody should do); ten minutes later, if you stick a piece of pH paper into the same spot of oceanwater you will get the pH of the ocean and not the acid. External pH cannot be the driving force in such a situation. Yet, protons are driven through the proton ion channel to make ATP just the same...so the conclusion was reached that it actually was the negative membrane potential (with a small effect in proton concentration differences) that largely seems to pull the protons in. Of course, if you gave that answer in your typical college class on a test you will probably be marked wrong (even if some of the more recent cell bio texts such as "The Cell" by Albert, Johnson, Lewis, etc. do implement this somewhat more modern view).

    The steep concentration gradient for calcium can be an exception to this as calcium channels are also used on internal membranes (such as the ER) that do not have the same strong membrane potential as the external plasma membrane does. Thus, two additional things are done so that the concentration term can dominate in the Gibbs for Ca in this instance: 1) Calcium is kept in a small sealed compartment (preventing the "ocean diffusion" idea from above and keeping the Ca concentration in the region of the channel very high), and 2) the concentration of Ca in the cytosol is kept extremely low. Of course, calcium can also function with ion channels on the external plasma membrane, and I suspect that as with Na,K, and Cl channels that in this instance once again the membrane potential become the dominant force over concentration, even for calcium.

    These sort of ideas about the electrical potential are out there now, but they do not seem to get the same amount of "press" as the concentration concept because concentration differences DO still contribute and it is simply much more easy to understand than a more full picture that takes into account electrical potentials from Physics (and hence, the poor poor chloride ion channel, which then runs counter to the "easy model" about concentration gradients and ion movement, gets regulated to the "zit" status as the tendency seems to be more about covering it up and hoping it will just go away rather than probing deeper into its function...).
  19. Aug 5, 2008 #18


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    I ask questions that seem important for the science community and it seems true that often I do not get any response. That is strange. I pointed out some basic violations of physics laws and the "faulty" drawings were removed from wikipedia because my argument was sufficiently strong.

    The question of this thread is of a similarly importance since sodium, that is a major contributor to action potential, enters the cell but do not go out before a long delay. That contradicts curves and curves do not lie. Na entered and just returned out. That is a lesson of conductances. If you make a derivation of the curve you obtain an internal shift immediately followed by an external motion.

    The theory must be refined. I have a theory that explains the fact, have you one that may explains this?

    I have many respect for Hodgkin and Huxley (the scientists) and they were pioneers in the domain and I remind some great words from them: Our theory is a very simplified way to explain how the things really happen. And it is true that some huge but necessarily truncations have been made because it wasn't impossible at the time to compute anything.
    Remember that a single pico second of a realistic ion channel computation takes several hours... Actually!
    Last edited: Aug 5, 2008
  20. Aug 5, 2008 #19
    Renge Ishyo, I read your recent post but I'm not sure how what you are describing is any different from our usual formalism for talking about these questions. That is, we calculate the reversal potentials of the various ions by the Nernst equation (or some variant thereof). Once you know the reversal potential and the concentrations of the various ions then for any voltage you know which direction the ions will be flowing. This is what you said a few posts up.

    This much was known before Hodgkin and Huxley. Their contribution can be viewed as the extension of this same formalism to the case where we have voltage gated ion channels. That is, the permeability of the ion is a function of the voltage.

    Somasimple, are you asking about the (mostly) k-channel mediated hyperpolarization that brings the membrane voltage back down after an action potential? Or are you asking about how the electrochemical gradients themselves are maintained? This occurs by pumps like the Na-K pump.

    I like what you said about the chlorine channel "completing the circuit" and maintaining charge neutrality. The AMPA channel has a reversal potential very close to 0 mV because it fluxes K, Na and Cl with differing permeabilities for each.
  21. Aug 5, 2008 #20


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    Neither the primer nor the later. I just want to know where the Na ions go when they entered the cell (since we suppose Na channels are closed/inactive). The Na/K pumps are too slow to reverse the situation and it is proved than blocking them do not implies an increase in internal Na+.

    The Na conductance gives matter to reflexion but we are in a condition where ions fluxes are supposed constant by the GHK equation (but not realistic).
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