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At what point during an action potential are the sodium potassium pumps working?

At what point during an action potential are the sodium potassium pumps working?


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I'm trying to understand how all of the potentials during an action potential are created. My question specifically is about the sodium potassium pumps, however I would also be grateful if someone could verify if I have grasped the concepts correctly.

From what I understand, the resting membrane potential is at around $-60 m,mV$, close to the equilibrium potential for potassium (from the Nernst equation) because the permeability of potassium is much greater than that of sodium, even though the permeability is low.

However, the resting potential is not as negative as the equilibrium potential for potassium because of some permeability of sodium and the permeability of potassium is very low so the tiny permeability of sodium has some impact in preventing the potential reaching the equilibrium potential of potassium.

When the threshold potential of $-50 m,mV$ is reached, the voltage gated $ce{Na+}$ ion channels open, and sodium ions enter the cell, causing depolarisation. The potential rises to about $+40 m,mV$, which is close to the equilibrium potential for sodium (because the permeability for sodium is much greater than for potassium). However, it doesn't quite reach the equilibrium potential for sodium because of some potassium ions leaving the cell.

When the $+40 m,mV$ threshold is reached, sodium channels close and potassium channels open. Because of the now much higher permeability of potassium ions compared with when the membrane is at its resting potential, the potential becomes much closer to the equilibrium potential for potassium, which I think is about $-90 m,mV$, and therefore the cell hyperpolarises. Then the potassium channels close.

Now I'm unsure as to how the resting membrane potential is reached from the hyper polarised state, and I also do not see where the action of the sodium potassium pumps comes into this.


The Sodium-Potassium Pumps are always at work. One can think of them as a continuous process that maintains the equilibrium potential for the individual ions. They always are grabbing internal sodium and exchanging it with external potassium at the cost of ATP.

However a neuron's rest state (in your example -60 mV) is a combination of the equilibrium of the Sodium, Potassium, Chlorine, and other ions. Thus when the membrane hyperpolarizes beyond the rest potential, it is actually the leak potential that brings the membrane potential back up, not the Sodium-Potassium pump.

Leak potentials arise from ions (usually chorine) that pass through the membrane via channels that are always open. Furthermore, sodium channels reactivate and a small amount open to sodium to enter. (Recall as a population there is usually a small amount of sodium channels open at rest. Another contributing factor is as the potassium channels close the other to factors dominate and slowly bring the membrane back to rest state. Remember that rest is defined as the balance of currents, there will always be small amounts of currents flowing. So even though the neuron is rest small amounts of sodium leak in and less potassium out. The sodium potassium pump maintains the equilbrium potential that allows these currents to flow.

The Sodium-Potassium pump is a slower process, so it usually can be ignored over a single spike. But If there is a high frequency spike train then the small amount of sodium that enters the cell and potassium that exits the cell can add up and effect the equilibrium potentials of the individual Ions. This of course changes the firing properties of the neuron.


Very good question. Most of your arguments, to the best of my knowledge are accurate. As to answer your questions, I'll provide a basic model of understanding. (Disclaimer:- I'm sorry if the explanation seems overly-messed up and confusing)

At any moment, the potential difference across the cell membrane has to be such that it makes all fluxes balanced. Let us assume there is a cell with nothing but potassium and non-diffusible negative porteins. Since potassium is the only ion that can have a flux, the only balanced position will be the one with zero flux, because any net ionic movement will cause a change of potential and hence will not be the balanced state. Zero flux will be reached when the concentration ratio of potassium outside and inside is such that the potential difference is equal to potassium's Nernst potential.

To complicate it, let's add sodium. Now the balanced state should have zero net flux. But this does not mean that the fluxes of both the ions is zero. They can be equal and opposite. Let us assume that the permeability of the membrane is equal for both. Then, the balanced potential would be equidistant from the Nernst potential of both the ions. This is because, permeability, in an abstract way, is a measure of the resistance. Flux is the potential difference (between the Nernst potential, where the flux would be zero, and the membrane potential) divided by the resistance (like a simple current), which would be equal only if this difference is same, which is, for a membrane potential midway between their Nernst potentials. Hence, the ion which has a higher permeability, will have a lesser resistance, and would hence require the potential difference to be low, so that the ratio of $PD$ and $R$ be equal to the other ion with a large $PD$ and a high $R$ (low permeability). This $PD$, is not the membrane potential but the difference between this potential and the Nernst potential.

Now, for your first question

… resting membrane potential is reached from the hyper polarised state…

This is simple to understand because the opening of the potassium channels which caused the potential drop to $-90$ has now been reset and the permeabilities have been reset to the original resting values. Since the balanced state depends on the permebilities only, the balanced state of this is the RMP ($-60$), which the cell will achieve. Since $-90$ is unbalanced, the slightly unbalanced flux will cause a drift of the potential towards $-60$ and when it reaches it, the fluxes will match and hence won't deviate any further. The drift is because more of one ion is moving than the other, causing a net movement of charges across the membrane.

… action of the sodium potassium pumps comes into this…

This is easy to understand but tough to compute. Since the sodium potassium pump is unbalanced, (it puts out 3 sodiums and takes in 2 potassiums), it contributes a net flux always. Hence, the remaining channels, instead of having exactly equal sodium potassium fluxes, will have to have a slight potassium excess to offset the minor flux contributed by the pump. As a result, the effect can be computed in two ways.

  1. We find the net flux contribution of the pump. Now we know by what amount should the potassium flux be greater than the sodium in the remainign channels which follow the PD/R formula and hence we can caluclate the PD such that the fluxes have a certain difference (equal to the flux contributed by the pump)

  2. We perform experiments and directly find a net amount of potential "correction" which has to be added to the potential calculated by matching fluxes because of the pump, which will remarkably stay constant. This method is easier and the value of the correction can be obtained from literature online.

Hope this helped. Feel free to ask for clarifications. If you want net links or references, ask. :)


First in a series on hyperkalemia: hyperkalemia, the sodium potassium pump and the heart

The sodium potassium ATPase pump enzyme found in the sarcolemmal membrane of cells keeps 98% of potassium intracellularly by actively pumping two potassium ions into the cell while ousting three sodium ions. Under normal conditions homeostasis is maintained between potassium intake, intra/extracellular shifts and potassium excretion. A disturbance producing hyperkalemia has been recorded in up to 10% of hospitalized patients. The gravity of severe hyperkalemia lies in the dire consequences of its ramification on the action potential, resulting in dysrhythmias and cardiac arrest. Controlling the functionality of the sodium potassium pump could rewrite the guidelines for cardiopulmonary resuscitation (CPR) and cardiac arrest management.

Background

Potassium is a soft, silvery-white highly reactive cation belonging to the alkali metal group family in the periodic table. It is the most abundant cation in the human body as a whole, and the most widespread ion in its intracellular compartments.

On average, a western diet contains from 80-100 mEq of potassium per day, and under normal physiologic conditions, 90% of it is absorbed passively, leaving only 9.0 mmol for fecal excretion. The 3500-4000 mmol kept stored in the body are disproportionate to the diurnal plasma potassium levels which are normally maintained in the range of 3.5-5.3 mmol/L through a tight homeostasis mechanisms with the lowest levels being at night and in the early morning hours and the highest peak level in the afternoon hours. [1]

Once absorbed into the blood stream, it becomes the role of the kidney to match potassium intake to potassium output requiring several hours, during which time the &ldquointernal potassium balance&rdquo under the influence of insulin and catecholamines maintains temporary homeostasis by shifting the potassium between the intracellular and extracellular spaces. Stimulation of the alpha receptors impairs potassium entry into the cells, and stimulation of the beta receptors promotes it by activating the sodium potassium ATPase pump.

The sodium-potassium ATPase pump is the gate-keeper enzyme located in the sarcolemma. It helps to safeguard 98% of potassium (approximately 144.0 mmol) retained inside the cell. This ensures the preservation of the vital potential difference across the cell membranes needed for proper cell function, especially the excitable cells such as nerve cells and the cardiac muscle cells. [2,3,4]

Normal physiology and pathophysiology of potassium

After its rapid absorption, potassium helps orchestrate its own body levels through the release of insulin and aldosterone. Other inherent body stimuli also found to control potassium body levels include beta-2 adrenergic receptors, alkaline blood PH, and cellular anabolism.

Release of Insulin and Aldosterone: Ingested potassium rapidly enters circulation. On reaching the portal circulation, it stimulates the pancreas to release insulin. Concurrently, the circulating potassium reaching the juxtaglomerular cells results in the release of renin. Renin, on reaching the liver, is converted to angiotensin I. Angiotensin I travels to the lungs where it is converted into angiotensin II. Angiotensin II then completes its journey back to the kidneys through the circulating blood to stimulate the zona glomerulosa to secrete aldosterone.

Internal Potassium Balance: The insulin released post-prandially acts primarily on the skeletal muscles, activating two pathways, the AKT-dependent pathway responsible for the insertion of the glucose transporter GLUT4 and the APK pathway activating the cellular sodium potassium ATPase to shift the potassium into the intracellular space. Unlike the AKT-dependent pathway, the APK pathway is unimpaired by neither metabolic syndrome nor chronic kidney disease [4] (Figure 1).

Excretion: Potassium filtered by the renal glomeruli is passively reabsorbed in the proximal tubule and loop of Henle in proportion to the amount of sodium and water delivered. Normally only about 10% of the filtered load reach the distal nephron.

Figure 1. Action of insulin on a skeletal muscle cell. Insulin released post-prandially activates two pathways in skeletal muscles, the AKT-dependent pathway responsible for the insertion of the glucose transporter GLUT4 and the APK pathway activating the cellular sodium potassium ATPase to shift the potassium into the intracellular space.

At the beginning of the distal convoluted tubule, secretion of excess potassium commences and increases progressively as it advances further towards the distal nephron and into the collecting duct. This is mediated by the upregulation of hydrogen potassium ATPase on the alpha-intercalated cells [5].

The presence of higher potassium levels in the peritubular cells of the kidneys activates the RAAS system to release aldosterone, which activates the sodium potassium ATPase in the basolateral membrane, resulting in a decrease in the intracellular sodium which leads to the increased electrogenic transport of potassium uptake by hyperpolarizing the membrane voltage and allowing its excretion into urine [2].

In hyperkalemia, the quota of potassium excreted through the colon may increase by up to 30%, e.g., in cases of renal failure, where the potassium is then actively taken up by the activated sodium potassium ATPase pump in the colonic enterocytes&rsquo basolateral membrane, to be excreted on the other side, into the colonic lumen through the apical large calcium-dependent potassium channels of the cells.

It is thus discernible from the above that the mechanism of potassium plasma level homeostasis is ordained mainly by the interaction of three simultaneous transactions - potassium intake, potassium intra/extracellular shifts and potassium urinary excretion, all of which ultimately rely on the sodium potassium pump.

To comprehend the mechanism of imminent danger from hyperkalemia and its management, one must understand the physiology of the action potential and the innards of the sodium potassium ATPase enzyme.

Electrophysiology of the action potential, i.e., ionic movement across the cell membranes, is determined by the difference in two potentials, a &ldquochemical potential&rdquo in which the ions move down their concentration gradient and an &ldquoelectrical potential&rdquo in which ions and molecules repel like charges, yielding the transmembrane potential (TMP), which is said to be +ve when the net movement of +ve ions is to the outside of the cell and vice versa.

Action potential of a non-pacemaker cardiomyocyte

There are five phases to an action potential, which begin and end at phase 4. The pumps involved in this process include the sarcolemma sodium calcium exchanger, calcium ATPase and, ultimately, the sodium potassium ATPase.

  • Phase 4. The resting phase: this has a resting potential of -90 mV as a result of the constant outward movement of potassium via the inward rectifier channels. During this phase, both the sodium and calcium channels are closed.
  • Phase 0. The depolarization phase: the firing of a pacemaker cell or its conduction through a neighboring cell triggers the rise of TMP to above -90 mV. At this point , the &ldquofast sodium channels&rdquo start opening one by one, allowing sodium to enter into the cell, raising the TMP and, once enough fast sodium channels have opened to yield -70 mV, a self-sustaining inward sodium current is set into motion, rapidly depolarizing the TMP to 0 mV for a transient interim known as the "overshoot", at which point the time-dependent fast sodium channels close and the "long-opening&rdquo calcium channels open to raise the TMP to -40 mV and allow a small steady calcium influx down its concentration gradient.
  • Phase 1. The early repolarization phase: this starts with the slightly +ve TMP and the brief opening of some potassium channels resulting in its flow to the outside of the cell, returning the TMP back to approximately 0 mV.
  • Phase 2. The plateau phase: here the two counter currents are electrically balanced and result in the maintenance of the TMP balanced at just below 0 mV. &ldquoThe long-opening calcium channels&rdquo are still open, resulting in a constant calcium flow into the cell. The delayed rectifier potassium channel allows the passage of potassium to the outside of the cell down its concentration gradient.
  • Phase 3. The repolarization phase: during this phase, the calcium channels are gradually inactivated and the persistent flow of potassium to the outside of the cell thus exceeds the inward calcium flow, returning the potassium to the intracellular space and the sodium and calcium to the outside of the cell.

Action potential of a cardiac pacemaker cell

The cardiac pacemaker cells have an innate automaticity, allowing their depolarization in rhythmic cycles. The sinoatrial node (SAN) has the highest self-initiated depolarizing rhythm at a rate of 60-90/min, followed by the atrioventricular node (AVN) at a rate of 40-60/min and then the Purkinje fibers and ventricular muscle at 20-40/min.

The membrane potentials of pacemaker cells are unstable and their action potentials have no clear-cut phases. They have fewer inward rectifier potassium channels and their TMP never drops to below -60 mV, eliminating the role of the fast sodium channels that require a TMP of -90 mV resulting in the absence of the rapid depolarization phase.

At TMP >-60 mV, "funny/pacemaker" current is set into action with a spontaneous flow of ions through the slow sodium channels, depolarizing the TMP to <-50 mV and then back to -60 mV when the calcium channels close.

Current conduction

All the cardiomyocytes are electrically coupled through the gap junction, including the pacemaker cell. This facilitates the widespread depolarization of all neighboring cells, turning the heart into one functional unit in which the cell with the highest inherent rate becomes the "pacemaker".

Refractory period

The longer refractory period during the long plateau in phase 2 due to the slow calcium channels provides the time needed for the complete emptying of the ventricles before the next contraction. Refractory periods can be absolute (ARP), effective (ERP) or relative (RRP). In an ARP, the cell is absolutely unexcitable.

An ERP lasts from the ARP until the short segment of phase 3. A stimulus at this point could minimally depolarize the cell, but the level of depolarization is weaker than propagating an action potential to the neighboring cells.

RRP is brought about by an above normal stimulus, leading to the depolarization of the cell and the production of an action potential.

A &ldquosupra-normal period&rdquo is a hyperexcitable state during which a weaker than normal stimulus could lead to an arrhythmia, necessitating the synchronization during cardioversion to avoid ventricular fibrillation [6] (Figure 2).

Figure 2. Refractory Periods. ARP: Absolute Refractory Period ERP: Effective Refractory Period RRP: Relative Refractory Period SNR: Supranormal Refractory Period

Hyperkalemia, classification and causes

Classification

Hyperkalemia is classified as mild when levels are in the range of 5.5-6.0 mmol/L, moderate from 6.1-6.9 mmol/L and severe at levels of 7.0 mmol/L or greater, and at any level at which ECG changes occur [7].

Causes

Hyperkalemia occurs when compensatory mechanisms are no longer able to cope with the imbalance, which is why it is usually multifactorial.

  • Increase in the intake of potassium via any route, e.g., dietary oral intake, or intravenous administration of potassium containing fluids like penicillin G.
  • Retention by the kidneys: since potassium excretion depends on aldosterone and the delivery of a sufficient distal amount of sodium and water within the nephrons, conditions such as renal failure, adrenal insufficiency (Addison's disease) , hyporeninemic hypoaldosteronism type IV, renal tubular acidosis, especially in patients with diabetic nephropathy as well as any condition that promotes hypoperfusion as in volume depletion and congestive heart failure, will affect the intricate balance of potassium in the body and predispose to hyperkalemia.
  • Adrenal insufficiency: this must be excluded in hyperkalemic patients, particularly in the presence of hyponatremia and muscle weakness. To screen for primary adrenal Insufficiency, a standard cosyntropin stimulation test is performed in which 0.25 mg synthetic cosyntropin is given as an intravenous bolus followed by plasma cortisol measurement 45 minutes to 1 hour later. Values less than 20 mcg/dL are suggestive of adrenal insufficiency.
  • Drugs that retain potassium: prescription medication drugs which reduce sodium potassium ATPase activity such as beta-adrenergic receptor blockers, and drugs that reduce aldosterone secretion such as ACE and ARB inhibitors, non-steroidal anti-inflammatory drugs, and potassium-sparing diuretics, need close follow-up to avoid iatrogenic hyperkalemia, especially in the geriatric age group with their progressive decline in renal function as part of the aging process.
  • Perturbations in the transcellular shift of potassium: this may occur with conditions of acidosis, hyperglycemia, hyperosmolality, severe exercise, tissue breakdown, hyperkalemic periodic paralysis, and with beta-adrenergic blockers. For every 0.1 unit decrease in blood PH, serum potassium increases by about 0.6 mmol/L (less if the acidosis is caused by organic acids) [2].
  • Pseudo-hypoaldosteronism is a congenital autosomal recessive disease in which the kidneys are resistant to the actions of aldosterone.
  • Pseudo-hyperkalemia must also not be overlooked: as the name implies, this occurs when there is elevated serum potassium in the presence of normal plasma potassium. It may be seen in hemolyzed blood, prolonged tight tourniquet during a blood sampling procedure, causing the extracellular release of potassium, with repeated clenching of the fist during phlebotomy, traumatic venepuncture, with leukocytosis and thrombocytosis, and in some uncommon genetic syndromes such as familial pseudo-hyperkalemia and hereditary spherocytosis. However, it could simply just be a result of a simple laboratory error.

Effects of hyperkalemia

Mild hyperkalemia is often asymptomatic, detected accidentally by laboratory tests, due to its vague symptoms such as malaise, muscle weakness and paraesthesia. Severe hyperkalemia will affect the neuromuscular function in the form of skeletal muscle weakness and paralysis however, this is not a frequent presentation as the cardiac toxicity dominates the picture and is the preliminary presentation. Cardiac toxicity will usually present on the ECG in the following step-up escalating manner, although not necessarily so, depending on the etiology:

  • At levels greater than 5.5 mEq/L, the increase in the conductance of potassium channels increases lkr current, leading to rapid repolarization in the form of a peaked T wave on the surface ECG. These T waves can be differentiated from those of myocardial infarction and CVA by their short duration ranging from 150-250 msec.
  • At potassium levels greater than 6.5 mEq/L, a state of sustained subthreshold depolarization occurs, causing a delay in atrial and ventricular depolarization. The decrease in phase 0 of the action potential leads to a longer action potential, producing a delay in intraventricular and atrioventricular conduction. On the surface ECG, this will present with a flattening and loss of P waves and widening of QRS complexes. With increasing delay in the intraventricular conduction, the surface ECG starts to show signs of left and right bundle branch block. This can be differentiated from bundle branch disease by the fact that in hyperkalemia the delay persists throughout the QRS complex, not just during the initial or terminal portions, respectively.
  • At 10 mEq/L, sinoatrial conduction no longer occurs and the accelerated junctional rhythm takes over. Ventricular arrhythmias develop with merging of the widened QRS complexes with the T waves eventually to form the classic sine-wave pattern. Once this occurs, VF and asystole are imminent and cardiac arrest will then ensue.
  • Sometimes changes may be erratic and unpredictable and the ECG will jump from normal to asystole due to the variability in the etiological factors and their influential effects, e.g., rate of potassium change, calcium concentration, pH, and sodium concentration. Thus, hyperkalemia should be treated emergently whenever potassium levels become greater than 6.5 mmol/L, or in the presence of ECG manifestations of hyperkalemia regardless of the potassium level. Other reported associations with acute hyperkalemia include: picture of pseudo MI on the ECG recording, with massive ST-T segment as a result of derangements in myocyte repolarization, short PR and QT intervals, sinus tachycardia, sinus bradycardia, idioventricular rhythm, 1st and 2nd degree heart block [3].

Metabolic effects

Hyperkalemia leads to hyperchloremic metabolic acidosis as the hyperkalemia promotes the intracellular uptake of potassium in exchange for hydrogen ions. This creates intracellular alkalosis, suppressing kidney ammonia production in the proximal tubules, leading to a decrease in urinary ammonium and acid excretion and a type IV renal tubular acidosis [8].

Sodium potassium pump

The sodium potassium ATPase was discovered in 1957 by Skou, who was later awarded a share of the 1997 Nobel Prize in Chemistry for his discovery.

Skou was the first to discover the sodium potassium ATPase in the sarcolemma of the cardiac muscles' cell surface. Its presence was later detected in every eukaryotic single and multicellular organism.

The sodium potassium pump functions by linking the hydrolysis of ATP to the cellular export of three sodium ions in exchange for two potassium ions against their electrochemical gradients. It is the molecular target for digitalis and digoxin, which have been in use since the 18th century as foxglove extracts.

The action of the sodium potassium pump is regulated by a phosphoprotein phospholemman, whose unphosphorylation leads to the inhibition of the pump and whose phosphorylation leads to an increase in the pump activity. It has three phosphorylation sites, two palmitoylation sites and one glutathionylation site, which explains the multitude of signals capable of stimulating and inhibiting the pump.

The sodium potassium pump itself is an enzyme composed of multiple subunits with multiple isoforms. The presence of the alpha and beta subunits (mainly B1 in the heart) is essential for its function. Recently, a third protein gamma subunit has been identified in the kidneys, but to date its function remains unknown.

The alpha subunit is the catalytic core of the sodium potassium pump enzyme. It is approximately 100 kDa and contains the binding sites for sodium, potassium, ATP, and cardiotonic steroids such as ouabain. Only alpha 1 and alpha 2 display a significant presence in a normal cardiac myocyte and are functionally linked to the sodium calcium exchanger (NCX). Alpha 3 has been reported to replace alpha 2 in experimental heart failure models [2].

Data from recent experiments favor the involvement of both alpha 1 alpha 2 subunits of the pump in the regulation of the excitation-contraction (E-C) coupling. The alpha 1, which was found to be more evenly distributed across the sarcolemma, is thought to play more of a "housekeeping" role, controlling both contractility and the bulk intracellular sodium, while the alpha 2 whose expression is concentrated in the T-tubules along with other key components of E-C coupling is thought to focus mainly on contractility [2,9].

Known factors that can control the sodium potassium pump include: ATP, intracellular sodium, sub-sarcolemmal barriers and fuzzy spaces, membrane potential, intracellular signaling pathways (adrenergic signaling pathways, protein kinase A & C, nitric oxide, phospholemman), direct regulation by small molecules (lipids, endogenous cardiotonic steroids), other associated proteins (caveolae and caveolins, and ankyrin).

Conclusion

Hyperkalemia is a clinical challenge and may present in up to 10% of hospitalized patients [10]. Its end result is life-threatening. As all of the cells in the body are ultimately affected by the sodium potassium pump, and ischemic cardiac muscles are known to extrude their potassium extracellularly leading to a reduction in the arrhythmia threshold with the possibility of ventricular arrhythmias that aggravate the hypopolarization and lower the threshold even more, more studies need to be focused on the manipulation of the sodium potassium enzyme, as its control could favorably alter the outcomes of cardiac arrests and rewrite the current CPR guidelines.

References

  1. Steele A, deVeber H, Quaggin SE, Scheich A, Ethier J, Halperin ML. What is responsible for the diurnal variation in potassium excretion? Am J Physiol. 1994 Aug267(2 Pt 2): R554-60. http://www.ncbi.nlm.nih.gov/pubmed/?term=Am+J+Physiol.+1994+Aug%3B267(2+Pt+2)%3A+R554%E2%80%93R560.
  2. Allen J, Young D. Managing hyperkalaemic patients. Clinical Pharmacist, Vol. 1, p403 | URI: 10981128.http://www.pharmaceutical-journal.com/learning/learning-article/managing-hyperkalaemic-patients/10981128.article
  3. Parham WA, Mehdirad AA, Biermann KM, Fredman CS. Hyperkalemia revisited. Texas Heart Inst J. 200633(1):40-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=Texas+Heart+Inst+J.+2006%3B33%3A40%E2%80%937.
  4. Palmer BF. Regulation of Potassium Homeostasis. Clin J Am Soc Nephrol. 2015 Jun 510(6):1050-60. http://www.ncbi.nlm.nih.gov/pubmed/?term=Biff+F.+Palmer.+Regulation+of+Potassium+Homeostasis
  5. DuBose TD Jr, Codina J, Burges A, Pressley TA. Regulation of H(+)-K(+)-ATPase expression in kidney. Am J Physiol. 1995 Oct269(4 Pt 2):F500-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=Am+J+Physiol+269%3A+F500%E2%80%93F507%2C+1995Google+Scholar
  6. Ikonnikov G, Yelle D. Physiology of cardiac conduction and contractility.http://www.pathophys.org/physiology-of-cardiac-conduction-and-contractility/
  7. Macdonald JE, Struthers AD. What is the optimal serum potassium level in cardiovascular patients? J Am Coll Cardiol. 2004 Jan 2143(2):155-61. http://www.ncbi.nlm.nih.gov/pubmed/?term=J+Am+Coll+Cardiol.+2004%3B43(2)%3A155-161.
  8. Pfennig CL, Whitmore S, Slovis C. Focus On. Critical Decisions: Hyperkalemia. http://www.acep.org/Education/Continuing-Medical-Education-%28CME%29/Focus-On/Focus-On----Critical-Decisions--Hyperkalemia/
  9. Schwinger RH, Bundgaard H, Müller-Ehmsen J, Kjeldsen K. The Na, K-ATPase in the failing human heart. Cardiovasc Res. 2003 Mar 1557(4):913-20. http://www.ncbi.nlm.nih.gov/pubmed/12650869.
  10. Hollander-Rodriguez JC, Calvert JF Jr. Hyperkalemia. Am Fam Physician. 2006 Jan 1573(2):283-90. http://www.ncbi.nlm.nih.gov/pubmed/?term=Am+Fam+Physician.+2006+Jan+15%3B73(2)%3A283-90.

Notes to editor

Author:

Consultant Cardiologist, Past Egyptian Cardiology Board Fellowship Coordinator at the National Heart Institute


What is Action Potential? (with pictures)

Potential, or potential difference, occurs when there is a difference in electrical charge between two points. This difference in charge is usually due to a concentration of oppositely charged ions at each point. Action potential occurs when there is a sudden and sharp change in the potential difference across the membrane of a nerve cell that is propagated along the length of the cell.

When a nerve impulse is not being transmitted, the inside of the nerve cell has a negative charge and the outside a positive one. It is said to be in its resting state, so the potential difference at this time is the resting potential. The difference in charges is due to amounts of ions being found inside and surrounding the cell. In the case of nerve cells, the potential difference is due to sodium and potassium ions.

All nerve impulses are ionic in nature. When the nerve cell is at rest, there are different concentrations of the potassium and sodium ions on either side of the membrane. This difference is maintained by sodium-potassium pumps in the membrane. This pump pumps sodium ions out of the cell and potassium ions in.

Potassium and sodium ions diffuse across the membrane due to the difference in concentration on either side. Potassium ions can easily diffuse out of the cell, but the membrane is relatively impermeable to sodium ions diffusing in. The overall result is that the inside of the nerve cell has a negative charge relative to the outside of the cell.

When the nerve cell is stimulated and an impulse is initiated, the situation is momentarily reversed. The inside of the cell becomes positive and the outside negative. This sudden reversal of the resting potential that accompanies the impulse is the action potential. An action potential is extremely short-lived, so an impulse is actually a wave of depolarization, or action potentials, that passes along the cell.

During an impulse, the cell membrane becomes permeable to sodium ions. The sodium ions have a very high concentration outside the membrane, so they quickly diffuse into the cell. This takes place very rapidly and reverses the resting potential. With so many positive ions now found within the cell, the inside has a positive charge relative to the outside.

Sodium ions are able to enter the cell through ion channels. When the cell is resting, the ion channels remain closed and keep the sodium ions from entering the cell. When they are stimulated by an impulse, they open up and allow the inrush of the sodium ions. In this way, action potentials and impulses are self-propagating. The action potential in one area of the membrane stimulates the following area causing the ion channels to open. This in turn begins an action potential, which then stimulates the following area and so on.

As the sodium ions enter the cell, the potassium ions leave. This is the beginning of the recovery process where the inside of the cell begins to regain its negative charge. After the action potential has passed and moved along the cell membrane, the ion channels close and the membrane becomes impermeable to sodium ions. The sodium-potassium pump once again pumps the sodium ions out and potassium ions in, resulting in the resting potential being restored.


The Sodium-Potassium Pump

Active transport is the energy-requiring process of pumping molecules and ions across membranes “uphill” – against a concentration gradient. To move these molecules against their concentration gradient, a carrier protein is needed. Carrier proteins can work with a concentration gradient (during passive transport), but some carrier proteins can move solutes against the concentration gradient (from low concentration to high concentration), with an input of energy.

In active transport, as carrier proteins are used to move materials against their concentration gradient, these proteins are known as pumps. As in other types of cellular activities, ATP supplies the energy for most active transport. One way ATP powers active transport is by transferring a phosphate group directly to a carrier protein. This may cause the carrier protein to change its shape, which moves the molecule or ion to the other side of the membrane. An example of this type of active transport system, as shown in the figure below, is the sodium-potassium pump, which exchanges sodium ions for potassium ions across the plasma membrane of animal cells.

The sodium-potassium pump system moves sodium and potassium ions against large concentration gradients. It moves two potassium ions into the cell where potassium levels are high, and pumps three sodium ions out of the cell and into the extracellular fluid.

As is shown in the figure above, three sodium ions bind with the protein pump inside the cell. The carrier protein then gets energy from ATP and changes shape. In doing so, it pumps the three sodium ions out of the cell. At that point, two potassium ions from outside the cell bind to the protein pump. The potassium ions are then transported into the cell, and the process repeats. The sodium-potassium pump is found in the plasma membrane of almost every human cell and is common to all cellular life. It helps maintain cell potential and regulates cellular volume.

The Electrochemical Gradient

The active transport of ions across the membrane causes an electrical gradient to build up across the plasma membrane. The number of positively charged ions outside the cell is greater than the number of positively charged ions in the cytosol. This results in a relatively negative charge on the inside of the membrane, and a positive charge on the outside. This difference in charges causes a voltage across the membrane. Voltage is electrical potential energy that is caused by a separation of opposite charges, in this case across the membrane. The voltage across a membrane is called membrane potential. Membrane potential is very important for the conduction of electrical impulses along nerve cells.

Because the inside of the cell is negative compared to outside the cell, the membrane potential favors the movement of positively charged ions (cations) into the cell, and the movement of negative ions (anions) out of the cell. So, there are two forces that drive the diffusion of ions across the plasma membrane—a chemical force (the ions’ concentration gradient), and an electrical force (the effect of the membrane potential on the ions’ movement). These two forces working together are called an electrochemical gradient, and will be discussed in detail in “Nerve Cells” and “Nerve Impulses” concepts.


How does the ATPase pump work?

The sodium&ndashpotassium pump is found in many cell (plasma) membranes. Powered by ATP, the pump moves sodium and potassium ions in opposite directions, each against its concentration gradient. In a single cycle of the pump, three sodium ions are extruded from and two potassium ions are imported into the cell.

Also, what is the function of the Na +/ K+ pump? Na+/K+ ATPase pump The main function of the N+/K+ ATPase pump is to maintain resting potential so that the cells will be keeping in a state of a low concentration of sodium ions and high levels of potassium ions within the cell (intracellular).

In this regard, what is the function of ATPase?

ATPases are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur.

Why do cells swell up if Na K pumps stop working?

Every cycle of an Na/K pump removes three cations (3 Na+) for every two (2 K+) that it imports into the cell. Thus there is a net loss of one cation for every cycle of the pump. Therefore, without these pumps, the cell swells up.


Describe the sequence of events that create an action potential

Before an action potential can even start, it is important to remember that there are already uneven concentrations of ions over the membrane. Potassium ions are at a higher concentration inside the cell, while sodium ions are at a higher concentration outside the cell. The membrane is also more permeable to potassium ions than to sodium ions so potassium ions move down their concentration gradient to leave the cell at a greater rate than sodium ions enter the cell, and this leads to a potential difference being set up across the membrane of about -70mV. Because the membrane is more permeable to potassium ions, this is closer to the equilibrium potential for potassium, though it is influenced by the presence of sodium ions and other anions.

An action potential begins when voltage gated sodium ion channels, known as Na(V) channels open. This leads to an influx of sodium ions (moving down their concentration gradient), and the cell membrane begins to depolarise. This leads to the opening of more Na(V) channels, so the membrane depolarises even further. This continues until all of the available Na(V) channels are open, and the action potential reaches a peak of about +40mV. The more positive potential difference then causes the channels to deactivate, so that no more sodium can enter the cell. As the polarity of the cell membrane reverses, voltage-gated potassium channels also open, leading to an outward flow of potassium ions. These stay open even as the Na(V) channels inactivate, so that the membrane potential becomes more negative again, and in fact "overshoots" the resting potential of -70mV to around -90mV. This point in time is known as the refractory period, when action potentials can no longer fire. The resting potential is restored by the sodium-potassium pump, which continuously pumps out three sodium ions for every 2 potassium ions.


What is true about sodium potassium pump?

The sodium potassium pump (NaK pump) is vital to numerous bodily processes, such as nerve cell signaling, heart contractions, and kidney functions. The NaK pump is a specialized type of transport protein found in your cell membranes. NaK pumps function to create a gradient between Na and K ions.

Secondly, why is the sodium potassium pump important to the human body? The sodium-potassium pump is integral in maintaining the acid-base balance as well as in healthy kidney function. This energy is used to remove acid from the body. The sodium-potassium pump also functions to maintain the electrical charge within the cell. This is particularly important to muscle and nerve cells.

Herein, what are the steps of the sodium potassium pump?

  • 3 sodium ions bind to the pump.
  • A phosphate from ATP is donated to the pump (energy used)
  • Pump changes shape and releases sodium ions outside of the cell.
  • 2 potassium ions bind to the pump and are transferred into the cell.
  • Phosphate group is released and pump returns to its original shape.

How does the sodium potassium pump use ATP?

The sodium-potassium pump uses active transport to move molecules from a high concentration to a low concentration. The sodium-potassium pump moves sodium ions out of and potassium ions into the cell. This pump is powered by ATP. For each ATP that is broken down, 3 sodium ions move out and 2 potassium ions move in.


At what point during an action potential are the sodium potassium pumps working? - Biology

Part 1: Multiple choice. Answer on a scantron form. Each question is worth two points.

1. The “fluid” and “mosaic” terms in the fluid mosaic model of membrane structure refer to the ___ and ___, respectively.
A. inside of the membrane outside of the membrane
B. lipids proteins
C. proteins lipids
D. fatty acid chains polar groups


2. Which of the following proteins is likely to contain one or more hydrophobic segments, 20-30 amino acids long?
A. Integral membrane protein.
B. Peripheral membrane protein.
C. Lipid-anchored protein.
D. Cytoplasmic protein.


3. Which of the following would most readily cross a lipid bilayer by simple diffusion?
A. Oxygen
B. Glucose
C. Chloride ions
D. Proteins


4. The voltage-gated potassium channels associated with an action potential provide an example of what type of membrane transport?
A. Simple diffusion.
B. Facilitated diffusion.
C. Coupled transport.
D. Active transport.


5. You are studying the entry of a small molecule into red blood cells. You determine the rate of movement across the membrane under a variety of conditions and make the following observations:
i. The molecules can move across the membrane in either direction.
ii. The molecules always move down their concentration gradient.
iii. No energy source is required for the molecules to move across the membrane.
iv. As the difference in concentration across the membrane increases, the rate of transport reaches a maximum.
The mechanism used to get this molecule across the membrane is most likely:
A. simple diffusion.
B. facilitated diffusion.
C. active transport.
D. There is not enough information to determine a mechanism.


6. A particular cell has an internal chloride ion concentration of 50 mM, while outside the cell the chloride ion concentration is 100 mM. The free energy change associated with chloride transport into the cell (DG) is +970 cal/mol. Which choice below is the best explanation for this data?
A. Cl- ion movement into the cell is energetically favorable.
B. Both the concentration gradient and electrical gradient favor movement of Cl- ions into the cell.
C. The concentration gradient for Cl- ions favors movement into the cell, but the electrical gradient opposes inward movement of Cl-.
D. Both the electrical and chemical gradients for Cl- ions favor outward movement of Cl- ions.


7. Place the following steps in an action potential in the correct order.
1. Sodium channels become inactivated and potassium channels are opened.
2. Sodium and potassium channel gates are closed membrane potential is 㫔mV.
3. Sodium channel gates open in response to change in membrane potential.
4. Potassium rapidly leaves the cell membrane potential drops to 㫣mV.
5. Sodium rushes into the cell membrane potential reaches +40mV.
A. 2, 1, 4, 3, 5, 2.
B. 2, 1, 3, 4, 5, 2.
C. 2, 3, 4, 1, 5, 2.
D. 2, 3, 5, 1, 4, 2.


8. How are neurotransmitters released into a synapse in response to an action potential?
A. They pass through voltage-gated neurotransmitter channels.
B. They diffuse through the cell when the action potential reverses membrane potential.
C. They pass through gap junctions into the post-synaptic cell.
D. They are released by membrane fusion of vesicles in response to increased calcium concentration.


9. The neurotransmitter g-amino butyric acid (GABA) binds to receptors that are ligand-gated Cl- ion channels. What affect will this neurotransmitter have on the post-synaptic cell?
A. Cl- ions will rush into the cell leading to hyperpolarization and a reduced likelihood of an action potential.
B. Cl- ions will rush into the cell leading to depolarization and an increase in the chance for an action potential.
C. Cl- ions bind to GABA and inhibit it from interacting with the receptor, stimulating an action potential.
D. There will be no significant effect on the post-synaptic cell only the pre-synaptic cell is affected by neurotransmitters.


10. Which of the following is the most likely immediate affect of G-protein activation?
A. Receptors are stimulated to bind to their ligands.
B. Enzymes are activated that catalyze second messenger formation.
C. GTP is depleted from the cell.
D. G-proteins bind to DNA and activate gene expression.


11. Proteins with SH2 domains are important in intracellular signaling pathways. What is the function of these domains?
A. They bind to activated tyrosine kinase receptors.
B. They bind to DNA and activate gene transcription.
C. They regulate the activity of voltage-gated ion channels.
D. They hydrolyze GTP to inactivate the pathway.


12. Platelet activation at the site of a wound is a example of:
A. endocrine signaling.
B. paracrine signaling.
C. intracellular receptor activation.
D. apoptosis.


13. Apoptosis is mediated by signal transduction pathways that lead to the programmed death of the cell. How is cell death achieved during apoptosis?
A. Aqueous channels form in the cell membranes leading to inward movement of water and lysis of the cell.
B. Gene expression is activated that leads to the synthesis of inhibitors of respiratory enzymes.
C. The Na+/K+ ATPase is inactivated, leading to the loss of membrane potential which the cell needs to survive.
D. Caspases are activated that lead to hydrolysis of many cellular macromolecules.


14. Which of the following statements is NOT true of tyrosine kinase-linked receptors?
A. Monomeric receptors are often induced to dimerize upon ligand binding.
B. The activated receptors attract and activate G proteins to continue the signal pathway.
C. The cytoplasmic side of the receptor contains a kinase enzyme domain that is activated upon ligand binding.
D. Activated receptors autophosphorylate themselves to attract SH2 domain proteins.


15.What mechanism is used to regulate the spontaneous assembly of collagen protein into a collagen fiber?
A. Different fibroblasts secrete different components for each collagen fiber.
B. Inhibitory protein domains are removed by an extracellular protease.
C. Covalent cross-links between proteins are only made outside the cell.
D. Complete collagen fibers are exported from the cell only as they are needed.


16. Which choice below describes the major function of proteoglycans in the extracellular matrix?
A. They provide a hydrated, gel-like medium for lubrication, cushioning, and embedding other ECM components.
B. They provide high strength fibers required to withstand mechanical stress.
C. They provide a highly elastic support to resist tension.
D. They create the dense, hard support structures of bone tissue.


17. Fibroblasts attach the extracellular matrix to the cytoskeleton via:
A. focal adhesions.
B. tight junctions.
C. hemidesmosomes.
D. gap junctions.


18. Which of the following classes of molecules is not involved in direct cell-to-cell contact?
A. Cadherins
B. N-CAMs
C. Selectins
D. Fibronectins


19. The cell junction that prevents the two different types of glucose transporters from mixing in the plasma membrane of intestinal epithelial cells is the:
A. gap junction.
B. tight junction.
C. adherens junction.
D. desmosome.


20. Polarized epithelial cells:
A. have a reversed membrane potential from most other cells.
B. maintain distinct membrane domains through the action of tight junctions.
C. do not have gap junctions so they are isolated from their neighbors.
D. are found only in animals such as polar bears, walruses and penguins.

PART 2: Answer in the space provided. Points are in ( ).

1. (10 points) List and describe three types of membrane transport proteins. EXTRA CREDIT: Provide a specific example of each type (1 point each).

Carrier proteins - exist in two conformations, altered by high affinity binding of the transported molecule. Moves material in either direction, down concentration gradient (facilitated diffusion). EXAMPLE: GluT1 erythrocyte glucose transporter.

Channel proteins - primarily for ion transport. Form an aqueous pore through the lipid bilayer. May be gated. Moves material in either direction, down concentration gradient (facilitated diffusion). EXAMPLES: Voltage-gated sodium channel, erytrhocyte bicarbonate exchange protein.

Active transporters - use energy (direct, ATPase or indirect, ion gradient) to drive molecules across the membrane against a concentration gradient. EXAMPLES: Na+/K+ ATPase, Na+/glucose transporter.

2. (10 points) Describe how a resting membrane potential is established and maintained.

The Na+/K+ ATPase pump moves K+ions into the cell and Na+ ions out of the cell to establish strong chemical gradients for each. The cell still maintains near electrical neutrality (K+ balanced inside by large anions, Na+ balanced outside by Cl-). Leaky K+ channels allow some K+ ions to flow out of cell, down chemical concentration gradient. This creates an electrical potential, as positive charges are leaving the cell. This electrical gradient favors movement of K+ back into the cell, setting up an electrochemical equilibrium for K+, typically at about -60 mV.


3. (10 points) Describe the difference between “open”, “closed” and “inactivated” voltage-gated sodium channels. Include in your answer the role of each state in generating an action potential.

Closed channels have an internal, voltage sensitive gate that is closed. Na+ ions are prevented from entering the cell by the closed gate. This state exists during the resting membrane potential. The channel is poised to respond to a signal.

Open channels have responded to a change in membrane potential by opening the internal gate. This is a protein conformational change in response to electrical changes. Na+ ions rapidly enter the cell, leading to depolarization and potentially to an action potential.

Channels are inactivated in response to an action potential. A protein domain blocks the exit to the channel, preventing the flow of Na+ ions.This allows the cell to restore the resting potential, and allows directional travel of the action potential by preventing another signal from occurring too soon.


4. (15 points) List and describe five different types of molecules that participate in signal transduction pathways.

Primary messengers/signal - bind receptors to intiate a cellular response pathway.

Tyrosine kinase receptors - plasma membrane receptors that transmit an external signal to the cell interior by autophosphorylation.

G-protein coupled receptors - ligand binding activates intracellular G proteins to trigger a pathway.

G proteins - activated by ligand-bound receptors. Trimeric, inactive receptors are induced to uncouple into alpha and beta-gamma subunits, as a result of the alpha subunit exchanging GDP for GTP.

SH domain proteins - bind to activated tyrosine kinase receptors to continue a pathway.

adenylyl cyclase/phosholipase C - examples of G protein targets that synthesize second messengers.

Second messengers - small molecules synthesized in response to a signal. Rapidly spread throughout a cell. Includes cAMP, Ca2+, IP3, DAG, NO, etc.

Ser/Thr kinases (MAP kinases) - a cascade of protein activation that amplifies signals and leads to cellular changes.

Transcription factors - activated by upstream events to alter cellular gene expression.

5. (15 points) List and describe five different types of molecules that function as part of the extracellular matrix.

Collagen - forms high-strength fibers of the ECM to provide a strong support network.

Elastin - covalent linkages and stretchable structures provide an elastic component to ECM that undergoes extensive expansion/contraction.

Fibronectin - binds to many other cell surface and ECM components, and links with the cytoskeleton to help model cell shape and participate in cell movement.

Proteoglycans - composed of polysaccharides and proteins. Carbohydrate components are often acidic and sulfated to attract and retain water. Provides a soluble matrix for other ECM materials, and provides cushioning and lubrication function.

Integrins - integral membrane receptors that bind to components of the ECM.

Laminin - an ECM component of the basal lamina, providing a support structure for epithelial cells.

Lectins, selectins, N-CAMs, Cadherins, etc. - provide mechanisms for cell-cell interactions.


Why is the sodium-potassium pump important?

The sodium potassium pump is important for the functioning of most cellular processes.

Explanation:

It is a specialised transport protein found in the cell membranes. It is responsible for movement of potassium ions into the cell while simultaneously moving sodium ions into the cell. This is important for cell physiology.

It has special significance for excitable cells such as nervous cells, which depend upon this pump for responding to stimuli and transmitting impulses. Transmission of nerve cells would've been impossible without the aid of this pump.

The sodium/potassium helps maintain resting potential,effect transport and regulate cellular volume. It also functions as a signal transducer/ integrator to regulate MAPK pathway, as well as intracellular calcium.

In the kidneys the sodium potassium pump helps to maintain the sodium and potassium balance.

It also plays a role in maintaining blood pressure and control cardiac contractions.


Incorporate Sources of Potassium

According to the Dietary Supplement Label Database, the recommended daily dose of potassium for adults is 4,700 milligrams. This can be easily achieved by consuming meat like steak, pork and chicken, as well as seafood like salmon, cod and sardines.

Fruits and vegetables are also good sources of potassium, with high amounts found in broccoli — a 100 gram serving of raw broccoli has approximately 316 milligrams of potassium — along with potatoes, tomatoes, bananas, kiwis and apricots. Dairy products all contain high amounts of potassium, with an 8-ounce serving of whole milk yogurt offering 352 milligrams of potassium.

For nuts, the highest amount of potassium is found in coconut water, the liquid present inside fresh, whole coconuts. A cup of coconut water offers 600mg of potassium, which is equivalent to 13% of daily value. The USDA explains that while fruits and vegetables provide a better source of potassium, nuts and seeds like hemp seeds and pistachios also serve as acceptable alternatives when needed.


Watch the video: Βήμα προς βήμα η αναζήτηση των καινούργιων συχνοτήτων στις τηλεοράσεις σας (September 2022).


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