The sodium-potassium pump is one of the most important systems within your nervous system. It’s a protein structure that sits within the cell membrane, but what exactly does it do?
The sodium-potassium pump is a mechanism found within cells whose goal is to transport sodium and potassium ions in opposite directions against a concentration gradient using Adenosine triphosphate or ATP. The purpose of the pump mechanism is to maintain a proper concentration of potassium ions.
But this is just the basic overview of what the sodium-potassium pump does daily – let’s see how it functions, the mechanism involved, and how it is regulated.
The Sodium-Potassium Pump Mechanism
When resting, sodium leaks into the cells, and potassium leaks out of the cell due to natural electrochemical forces.
It remains this way until an action potential is generated.
When an action potential reaches a specific sodium-potassium pump, sodium enters the cell (or becomes intracellular), and potassium leaves it (or becomes extracellular).
This process is thanks to Adenosine triphosphate, or ATP, a source of energy for cells.
The ATP consists of a nucleoside triphosphate which consists of adenine (a nitrogenous base), a ribose sugar, and three bonded phosphate groups.
There are four processes involved in the sodium-potassium pump:
- First, the pump binds three sodium ions to one ATP molecule.
- When the ATP splits, energy is provided to the pump to change the shape of the channel – driving sodium ions through the channel.
- When sodium ions are transported outside the cell membrane, the new shape of the pump channel allows two potassium ions to bind to it.
- When the potassium ions have entered the cell, the pump channel returns to its original form
The small number of ions moving across the sarcolemmal membrane in an action potential is quite small paralleled to the total number of ions.
Only once multiple action potentials have been generated will there be a significant difference in the extracellular and intracellular concentration of the respective ions.
The pump also has a higher affinity for sodium than potassium, resulting in ATP binding three intracellular sodium ions.
When an action potential moves the sodium and potassium in opposite directions against the cell concentration gradient, the three intracellularly bound sodium ions and the two potassium ions are swopped.
This means that when sodium moves out, potassium moves in.
For every generated action potential, this cycle restarts until the desired effect of muscle contraction is achieved.
The Function Of The Sodium-Potassium Pump
The Na⁺/K⁺-ATPase, or sodium-potassium pump, is a part of the cell structure and helps to maintain and regulate:
- Resting potential
- Transport
- Cellular volume
Alongside this, the sodium-potassium pump also signals integrators that control the Mitogen-Activated Protein Kinase (MAPK) Pathway, intracellular calcium, and reactive oxygen species.
All cells within the human body use most of the ATP they produce in order to maintain their sodium (Na+) and potassium (K+) concentration gradients.
In neurons specifically, the sodium-potassium pump is responsible for almost three-quarters of the cell’s energy use.
In other types of tissue, ATP consumption by the sodium-potassium pump has been related to glycolysis – the process in which glucose is broken down to produce energy.
Glycolysis was first discovered in red blood cells and was later found in renal cells by Sanders and co, smooth muscles by Lynch and Co, and Purkinje cells by Glitsch and Co.
These discoveries have contributed to proving the importance of the sodium-potassium pump in skeletal muscles where inhibited glycogen breakdown results in reduced pump activity and, therefore, a lower muscle force production.
The sodium-potassium pump has various functions in various ways – let’s look more closely at what exactly happens in this protein cell.
The Resting Potential Of A Cell
The sodium-potassium pump and diffusion of ions across membranes maintain the resting potential within the cell.
Resting potential refers to the imbalance of charges that exist between interior excitable neurons, or nerve cells, and their surroundings.
The resting potential of excitable cells lies in the range of -60 millivolts to -95 millivolts – with the inside of the cell negatively charged.
When the inside of the cell’s potential is greater than the resting potential (electronegative), the membrane of the cell becomes hyperpolarized.
In the case that the cell’s potential decreases to the point where it’s below the resting potential, it becomes depolarized.
To keep the membrane potential constant, the cell must have a low concentration of sodium ions and higher levels of potassium ions.
To achieve this, the sodium-potassium pump moves 3 sodium ions out when moving 2 potassium ions in – removing one positive charge from the intracellular space.
Additionally, there is a shortcut for the potassium in the membrane or a highly K-permeable ion channel which allows the voltage across the membrane to be close to the reversal potential.
What Is Reversal Potential?
The Nernst potential or reversal potential occurs when it is equally charged on either side of the membrane – meaning that there is no flow of ions between the membrane.
Even when potassium and sodium ions have the same charge, they will still have different equilibrium potentials for inside and outside the cell.
The sodium-potassium pump allows the membrane to reach nonequilibrium relative to the amount of sodium and potassium inside or outside the cell.
For example, the potassium concentration inside the cell is 100mM, compared to sodium, which is 10mM.
However, outside the cell, the potassium concentration is 5mM compared to 150mM sodium.
Transport Processes
When sodium ions leave the cell, it creates an environment for several secondary active transporters to use the sodium ion gradient.
Some of these secondary active transporters include membrane transport proteins which import amino acids, nutrients, and glucose into the cell.
The sodium-potassium pump also provides a sodium gradient involved in carrier processes like in the gut, for example.
In the gut, sodium is transported out of the cell and into the blood via the sodium-potassium pump.
The sodium-glucose symporter uses the sodium gradient to import sodium and glucose on the lumenal or reabsorbing side.
This process is a far more effective than simple diffusion, and similar processes occur in the tubular parts of the renal system.
The kidneys have a high level of sodium-potassium pump proteins within the distal convoluted tubule – these work to express up to 50 million pump actions per cell. (National Library of Medicine)
The pump is especially important in this system because it allows the kidneys to filter waste products out of the blood through the sodium gradient.
The sodium-potassium pump also permits the following in the kidneys:
- Reabsorption of amino acids
- Reabsorption of glucose
- Electrolyte regulation
- pH maintenance
The male reproductive organs also utilize the sodium-potassium pump to regulate membrane potential and ions required for sperm to move and function during egg penetration.
Additionally, the brain also relies on the sodium-potassium pump as neurons require it to reverse postsynaptic sodium flux to re-establish potassium and sodium gradients needed to fire action potentials.
Astrocytes, a sub-type of glial cells in the central nervous system, also require the sodium-potassium pump to maintain the sodium gradient, which maintains the neurotransmitter reuptake process.
How The Sodium-Potassium Pump Controls Cell Volume
If the sodium-potassium pump fails, it can result in cell swelling.
A cell’s osmolarity is the sum of the various concentrations of the cell's ions, proteins, and other organic components.
Without an effective pump, the cell will swell and rupture.
The sodium-potassium pump ensures the cell maintains the correct concentration of ions and other organic matter.
The Sodium-Potassium Pump Functioning As A Signal Transducer
Signal transduction is a very important process within cells.
It’s the process whereby chemical or physical signals are transmitted through molecular events.
Most often, these events will be caused by protein phosphorylation catalyzed by protein kinases – resulting in cellular response.
Recent studies, at least compared to 1957, looked at the mechanisms through which the sodium-potassium pump communicates with the nucleus within cells to transduce signals.
A 2002 study by Xie and co found that in addition to transporting ions across the membrane through action potentials, the sodium-potassium pump interacts with fellow membrane proteins to send messages to intracellular organelles.
Many labs have demonstrated that the sodium-potassium pump can also relay extracellular ouabain – a cardiac glycoside used to treat congestive heart failure – signals into the cell through regulating protein tyrosine phosphorylation.
Protein phosphorylation is the process of activating or deactivating enzymes by attaching a phosphate group to a molecule or ion.
A study by Ramnanan and Storey studied the sodium-potassium pump in land snails.
They found that reversible phosphorylation can provide a means to coordinate ATP use with ATP generation through catabolic pathways in aestivating land snails, which can be greatly beneficial in future studies.
Another important interaction in the sodium-potassium pump is how proteins interact with one another in pump-mediated transduction.
The sodium-potassium pump interacts directly with Src to form a signal-receptor complex.
Src is a non-receptor protein tyrosine kinase that transduces signals involved in controlling proliferation, differentiation, motility, and adhesion. (Nature)
The sodium-potassium pump initially inhibits Src, but the Src kinase is released and activated upon ouabain binding.
How The Sodium-Potassium Pump Controls Neuron Activity States
The sodium-potassium pump controls and sets intrinsic activity modes of both cerebellar Purkinje neurons and accessory olfactory bulb mitral cells.
This information suggests that the sodium-potassium pump might not only be responsible for maintaining gradients – but also for certain computational elements in the brain.
In fact, it’s been indicated that mutations within the sodium-potassium pump cause dystonia-parkinsonism – indicating its pathology of cerebellar computation.
Additionally, ouabain blockages in the sodium-potassium pump in a live mouse resulted in the mouse displaying dystonia and ataxia.
Alcohol inhibits the pump in the cerebellum and is likely how cerebellar computation and body coordination is corrupted.
Regulation Of The Sodium-Potassium Pump
Regulation in any system is important to ensure it works the way it should.
For example, the sodium-potassium pump needs to be regulated in skeletal muscle.
Continual stimulation of muscles – during exercise, for example – results in a dissipation of the cation gradient required for muscle contraction.
To offset the excessive release of sodium from the muscle cells, the sodium-potassium pump activates rapidly to delay the beginning of muscular fatigue and reduce potentially toxic levels of sodium intracellularly. (Physiology Journals)
There are two ways the Sodium-potassium pump regulates: Endogenous and Exogenous.
Endogenous
The sodium-potassium pump is upregulated by cyclic adenosine monophosphate (cAMP).
Some substances cause an increase in cAMP, like the ligands of the Gs alpha subunit, while others inhibit cAMP and, therefore, the sodium-potassium pump.
Exogenous
The sodium-potassium pump can be pharmacologically modified by administrating drugs exogenously and can be modified with thyroid hormones, amongst others.
A good example of this is sodium-potassium pumps being targeted in cardiac cells to improve heart performance by increasing the heart’s contraction force.
This works by releasing calcium from the cardiac cells’ sarcoplasmic reticulum.
Immediately after the heart muscle contracts, that calcium found intracellularly is returned to a normal concentration by a carrier enzyme, causing the muscle to relax.
The Blaustein hypothesis states that the carrier enzyme uses the sodium gradient created by the sodium-potassium pump to remove calcium from inside the cell – which slows down the pump action and results in elevated calcium levels in the muscle.
Elevated calcium levels could be the reason for cardiac glycosides' long-term inotropic effect.
This hypothesis has some problems in that less than 5% of Na/K-ATPase molecules are inhibited – which is not enough to effectively impact intracellular concentration.
Pharmacologic Regulation Of The Sodium-Potassium Pump
In certain conditions like cardiac disease, the sodium-potassium pump needs to be pharmacologically inhibited.
A common inhibitor that is used is digoxin which binds to the outside part of an enzyme – or in this case, phosphorylated potassium, to transfer potassium inside the cell.
When the binding process occurs, alpha subunits are dephosphorylated and reduce some effects of cardiac disease.
In inhibiting the sodium-potassium pump, the sodium levels will increase intracellularly, increasing intracellular calcium concentration.
Higher concentrations of calcium force contractions – which is extremely beneficial in patients whose hearts aren’t pumping or not pumping hard enough.
This process is a temporary aid in dire situations and can be life-saving.
Conclusion
The sodium-potassium pump was first discovered 60 years ago, and since then, much research has been conducted into its function and pharmacological use.
The pump mechanism is controlled by sodium and potassium moving across the concentration gradient in cells, and an action potential generates the pump action.
A lot of research is still being done regarding the sodium-potassium pump.
Future studies into it may reveal some beneficial attributes to aid pharmacological actions and better understand the processes within the mechanism.
References:
https://en.wikipedia.org/wiki/Sodium%E2%80%93potassium_pump
https://pubmed.ncbi.nlm.nih.gov/324293/https://link.springer.com/chapter/10.1007/978-3-319-24750-2_2
