High Potassium Foods

High potassium foods, low potassium foods and associated potassium symptoms info

 

Low Sodium, High Potassium Diet And Kidneys

A high potassium sodium ratio in the diet has been shown to have many advantages. This has been especially shown for lowering blood pressure. However there are concerns about too high of a ratio, especially a concern about having too little salt in the diet. There have been medical articles written suggesting caution about going too low with sodium intake. These studies have been based mostly on patients who are ill and have cardiac problems. They probably do not apply to healthy people. There is no question that there are groups of people who can have an extremely low sodium intake and avoid hypertension.

The Yanomami

Yanomami Woman & Child
Yanomami Woman and Child

The Yanomami Indians of the Amazon have a diet that has almost no salt, is high in potassium, and is high in alkaline foods. They have virtually no hypertension. Their urinary potassium sodium ratio is over 150 to 1. And their urine is very low in chloride, which is a sign of alkaline urine.

However there are many differences between the Yanomami and modern mankind. It would not be possible to live a modern life and to live as the Yanomami. What is responsible for their ability to live on such a low sodium diet?

Potassium Sodium Ratio Control In The Kidney

One of the main considerations in balancing potassium and sodium in the body has been how the kidney controls sodium and potassium excretion. The major mechanism that has been studied is the sodium-potassium-ATPase pump in kidney cells. This cellular pump allows potassium and sodium to be excreted by exchanging potassium and sodium.

It does this through the pump’s interaction with two ion channels in kidney cells, the ENaC channel and ROMK channel. This mechanism can only allow a ratio of 0.67 potassium to be excreted for every sodium reabsorbed. So the question is how so much potassium can be eliminated by the kidney without an exchange for sodium. How can the kidney excrete 150 potassiums for every sodium it excretes?

A Recent Study

A recent study (1) helps to explain this. BK channels are potassium channels in the cell. In the kidney these channels secrete potassium into the urine. The majority of them are located in the intercalated cells (IC) of the distal nephron. It is also known that the BK channels secrete potassium independent of sodium, and independent of aldosterone. This is in contrast to the aldosterone stimulated ROMK channels which are involved in the ATPase exchange of sodium for potassium in the distal nephron.

The intercalated cells (IC) are kidney cells that have very few sodium-potassium-ATPase pumps. The IC are the main location where potassium is excreted into the urine. This study used knockout mice (with no BK channels in IC) and wild type mice (with normal channels) to determine the role of the BK channels. They put these mice on different diets. Then they studied the blood and urine, as well as doing microscopic studies on the intercalated cells (IC), to determine the effect on the BK channels.

The Diets

The control diet they used was regular mouse chow with a potassium to sodium ratio of 3.2. This is higher than the ratio of the typical Western diet.

The experimental diets had even higher potassium sodium ratios. The potassium sodium ratio for the normal sodium, high potassium diet was 26.5. For the low sodium, high potassium diet the ratio was 848. This ratio is much higher than any modern diet.

The researchers also varied the experimental diet to achieve a urine that would be acid or alkaline. To achieve a more alkaline urine, the researchers substituted bicarbonate and citrate (a bicarbonate precursor commonly found in food) for chloride in the diet.

What Happened In The Kidney?

They found an increase in the number of BK channels in the intercalated cells when the diet had a high potassium and high alkaline content. And they found that there was no buildup of potassium in the blood on the high potassium, high alkaline diet, even when the diet was the low sodium diet.

When the diet was high in potassium and also high in chloride the urine was acid. In this condition, there was an increase in BK channels, but the channels did not function. When the urine was acid, there was a high buildup of potassium in the blood.

The researchers also found that with the high potassium, high alkaline diet that there was more loss of potassium in the sweat and in the colon. BK channels are not just in kidney cells, but also are present in sweat cells and colon cells.

How Does This Study Apply To Me?

This study explains how the Yanomami can avoid a high buildup of potassium in their blood while on a diet with a high potassium sodium ratio. The food that they eat is high in potassium, and also is high in alkaline precursors so that they have a very alkaline urine. This combination is very conducive to a low blood pressure.

So to get a blood pressure like the Yanomami, you do not need to move to the Amazon jungle and live primitively. Just change your diet to a low sodium, high potassium, alkaline diet.
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1. Bicarbonate promotes BK-a/ß4-mediated K excretion in the renal distal nephron. Cornelius RJ, Wen D, Hatcher LI, Sansom SC. Am J Physiol Renal Physiol. 2012 Dec 1;303(11):F1563-71. doi: 10.1152/ajprenal.00490.2012. Epub 2012 Sep 19.

Epidemiological Studies And Diet

The most recent posts have been about the molecular biology of the high potassium foods diet. They have shown how the potassium sodium ratio affects every cell process, because this ratio controls the electric field of the cell. If the ratio is too far off, the electric field is too weak and the timing of cell processes is disturbed. No other healthy diet recommendations do this. They do not explain the basic molecular biology of the diet, but rely on epidemiological studies.

Bell Curve

Normal distribution of many epidemiological studies

There are many posts on this website about epidemiological studies that support the health promoting ideas of the high potassium foods diet. However these types of studies cannot determine what it is about a diet that makes it healthy. All they can do is say that the group eating a particular diet had fewer problems (heart attacks, strokes, or cancers for example) than another group eating the usual American diet.

These epidemiological studies are the types of studies that are usually quoted by the press and other media sources. The reason the press uses these types of studies is that they are easier to understand. They seem more significant because they involve humans and what they eat.

It is also easy to make claims beyond the actual findings of a study by saying that the findings imply something more. For example, people in France have less heart disease and drink more red wine than Americans. Wine has resveratrol. Therefore, resveratrol reduces heart disease.

But often epidemiological studies are at odds with each other. They result in what a recent study (1) refers to as the “here today, gone tomorrow nature of medical wisdom.”

Epidemiological Studies Today

This recent article (1) by a leading epidemiologist discusses the problems with modern epidemiological studies, and why such studies often differ in their conclusions. Early in the history of epidemiology – the golden era of epidemiology – there were very large associations of diseases with their causes. So even if a study were flawed, it would find an association that was true. The findings then could be used to design a plan to help the entire public.

But today most of the risks and associations are small, and the diseases they are studying are complex. Yet the mindset of the researchers and the tools that the researchers use are the same as those used during the golden era of epidemiology. A new approach is needed.

The early studies tackled major risk factors with large differences between those with disease and those free of disease. In the area of cancer, one of the earliest associations found was a 200 fold increase in scrotal cancer in chimney sweeps compared to the average man.

How Modern Epidemiological Studies Differ

Today the associations found in studies are much smaller. They are related to lifestyle, and they are concerning chronic diseases with a long induction period between risk exposure and disease presentation. When there is a long induction period, it is harder to see a causal link than when it is a short period.

The author felt that it was time to reevaluate the use of the usual types of epidemiological studies. The most commonly used are observational studies, such as case-control and cohort studies. These types of studies were felt to be appropriate for the first two major historical eras – the sanitary era and the infectious disease era.

During these two eras the induction periods were short. Disease occurred within a few days of exposure. Direct intervention led to quick and noticeable changes.

However today, with chronic disease, long induction periods, and small associations and risk factors, interventions take longer and require much larger numbers of participants to see noticeable results.

No Black Box

What has evolved is a black box paradigm. The risk shows up and goes into the black box, and the disease comes out the other side. Nobody knows what happened inside the box. There is no scientific explanation. There is a lack of what Austin Bradford Hill (see post here) would call plausibility and coherence.

The reason the recent posts on this website have been mostly about molecular biology is to show that the high potassium food diet satisfies Hill’s criteria of plausibility and coherence. These criteria mean that the importance of the potassium sodium ratio must be plausible with known biological facts and coherent with facts known about the disease. The posts discuss studies demonstrating those facts.

The era of observational studies identified major risks to health such as smoking, hypertension, hypercholesterolemia, and malnutrition. When there was a large association, such as smoking and lung cancer, even flawed studies were able to work. But today associations are smaller. Bias and confounding can affect cohort and case-control studies when the associations are small. Because of these problems, guiding hypotheses are needed.

A New Framework For Studies

For many studies today the evolutionary perspective can help provide such a guiding framework. One obvious area is in nutrition and physical activity. For studies involving nutrition and physical activity, observational data may result in systematic difficulties in group assembly. People who are concerned about their health tend to eat well and exercise. And they have other factors in common. Being better off economically and better educated are just two such factors. It becomes difficult to know which of these factors is the causal one. It becomes difficult to account for such confounders in an epidemiological study.

The author points out that there are many factors concerning diet and nutrition that are hardwired into us by nature. The preferences for energy dense foods and certain food tastes are hardwired because of scarcity during humankind’s evolution. The scarcity of salt is one such example. Likewise our biologic set up (the hardwiring), such as our body’s ability to balance sodium and potassium, means that many of our present day approaches will not work.

An Evolutionary Perspective

But having an evolutionary perspective can help guide against trying to fight these hardwired characteristics. The author gives a suggestion concerning weight loss. He suggests altering food taste and energy density of food in line with our hardwired nature. He feels this should work better than the usual approach of trying to revise our behavior to go against that hardwired nature.

For the potassium sodium ratio this would mean developing foods that have satisfactory taste, and satisfy the desire for energy density, while providing foods with a high potassium sodium ratio. This approach only worked somewhat in Finland, discussed here, because they only changed the potassium sodium ratio of food somewhat. In Finland they improved the potassium sodium ratio of food slightly and got a reduction in stroke and cardiovascular disease. Finland went from the highest mortality for strokes to having approximately the same mortality as the United States.

Much of the intervention in Finland was an attempt at behavioral modification. Rather than focusing on the potassium sodium ratio of food, Finland tried to educate the public about the risk factors emphasized at the time – smoking, exercise, saturated fat, and drinking.

Although these are still risk factors to consider, the most important factor is the dietary potassium sodium ratio. Today much is known about the potassium sodium ratio of food and how the ratio found in high potassium foods affects our bodies to prevent disease. It is no “black box paradigm,” but a well characterized, scientifically sound basis for action.
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1. Point-counterpoint. The triumph of the null hypothesis: epidemiology in an age of change. Maziak W. Int J Epidemiol. 2009 Apr;38(2):393-402. doi: 10.1093/ije/dyn268. Epub 2008 Dec 17.

Hydrogen Bond Network Of Potassium Channel

The potassium to sodium ratio in your diet is important because it helps to determine the potassium sodium ratio inside and outside of your cells’ membranes. This ratio inside and outside the membranes creates an electric field. The electric field is critical to the cell performing its proper functions.

Maintaining the proper ratio is important so that your cells can function at their best. The electric field in a cell can change many times a second. These changes are how the cell drives all of your cell processes. It works very much like an electric motor, which has a rotor that rotates as the electric field changes.

But instead of turning a rotor, the changes in electric field drive cell processes by changing the shapes of proteins inside the cell. When the electric field changes, the local forces holding the protein in a particular shape change and the protein may change shape.

Hydrogen Bond Quadruple AngewChemIntEd 1998 v37 p75

Dots represent hydrogen bonds


The change in these proteins’ shapes is determined by the strength of local bonds inside the protein. The protein is folded into multiple types of shapes depending upon these bonds inside the protein. The bonds can be several different types. The last few posts talked about salt bridges. Salt bridges are bonds that are composed of electrostatic bonds and hydrogen bonds.

But hydrogen bonds can affect protein shapes and cell processes completely on their own. Hydrogen bonds are abundant throughout a cell. They are composed of a single hydrogen atom that is in position between two other types of molecules. These other molecules have areas that are negatively charged. The positively charged hydrogen locates itself between the negative charges. Instead of being bond tightly like a covalent bond, the attraction is weaker and more easily broken.

When the electric field inside your cell changes, the strength of the bond between the hydrogen and the negatively charged areas changes. If the change in the electric field is enough, the shape of the protein determined by these hydrogen bonds will change.

Potassium Channels

Potassium channels are proteins that we have been discussing quite a bit in the last few posts. They allow potassium to move across the cell membranes, thus changing the electric field.

In recent posts we discussed a gate inside the cell that opens and closes the potassium channel. The gate depends upon changing the position of salt bridges to open and close the channel. The salt bridges shift from one position to another when the strength of the electric field changes.

Selectivity Filters

But there are other mechanisms besides gates that can open or close a potassium channel. One of the other mechanisms that can open or close a potassium channel is a change in its selectivity filter. A selectivity filter is located on one end of the channel. This filter keeps out other ions and allows only potassium to enter the channel.

This is not completely true because on rare occasions a smaller sodium will get through. The reason the smaller sodium ion does not get through all the time is because both sodium and potassium have water loosely attached to themselves.

The size of the chamber of the filter allows potassium and its attached water to just fit. The filter then strips the water off the potassium, so that only the potassium ion goes through.

The smaller sodium ion plus water is too far away from the part of the filter that strips the water when it enters the filter. So its water does not get stripped off. But the sodium ion plus water is larger than a naked potassium ion, and thus is too large to get through the pore in the channel.

The Function Of The Selectivity Filter

The present study (1) looked at what is important for proper function of the selectivity filter, so that potassium can get through when it is supposed to, and is blocked when it should be blocked. The structure of the selectivity filter is highly conserved among all the various types of potassium channels, which means its structure is very important for it to work properly.

The researchers asked, “What are the aspects of the filter’s structure that allow it to function properly?” Different parts of its structure were changed experimentally to find out if the change made any difference in function. One part of the filter has no hydrogen bonds and another part is made of a hydrogen bond network. The researchers investigated how important the hydrogen bond network is for proper function of the potassium channel.

They changed the amino acids in the protein of the selectivity filter. Some of the amino acids that were changed did not affect the hydrogen bond network in the selectivity filter, and some did. The researchers then applied electric fields that were similar to those found when the cells change their electric field during normal conditions.

They found that the functional structure of the selectivity filter was determined by the hydrogen bond network. As long as the ability to form hydrogen bonds was undisturbed by the amino acid that was changed, the filter functioned normally. This occurred when there were mutations that affected parts of the filter that were uninvolved with the hydrogen bond network.

However, this finding changed when the mutation involved amino acids that were part of the hydrogen bond network. If hydrogen bonds were not able to interact normally, the filter functioned abnormally. As a result the opening and closing of the filter was severely affected. Instead of a steady activity, the channel had long periods of inactivity followed by bursts of activity. Some abnormal medical conditions are associated with this type of activity.

Keep Your Cells Healthy

Our cells have developed many mechanisms to help keep a proper balance of potassium and sodium. There is a great deal of redundancy so that when one portion goes bad, other areas can make up for it. However, interacting with all the cell processes is the electric field of the cell. When this field is not optimal, the cell does not function as it should. Getting a high potassium sodium ratio in your daily diet will help your cells to maintain this electric field, and will help your cells to function optimally.
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1. A multipoint hydrogen-bond network underlying KcsA C-type inactivation. Cordero-Morales JF1, Jogini V, Chakrapani S, Perozo E. Biophys J. 2011 May 18;100(10):2387-93. doi: 10.1016/j.bpj.2011.01.073.

Bad Fats And Potassium Sodium Ratio

We are often told to avoid saturated fats, and to get good fats instead of bad fats in our diet. What are good fats and what is it about them that makes them good? And what do they have to do with high potassium foods?

Arachidic Acid

Cell Membranes Are Made Of Fat

The fats we eat go into the membranes of our cells. Proteins are located in these membranes, and go across the membrane from one side of the membrane to the other side. These proteins change shape to do the work of the cell to keep us healthy.

Two important types of proteins that cross the cell membranes are channels and pumps. The channels and pumps move potassium and sodium back and forth across the cell membranes. The difference in concentration of potassium and sodium inside and outside the cell creates an electric field. Changes in this electric field drive the work of the cell.

If the electric field cannot change quickly enough, the cell cannot do its work properly. For the electric field to change quickly, the channels and pumps must move potassium and sodium quickly.

The channels and pumps sit in cell membranes, which are composed of fats (lipids). The type of lipids in the cell membrane may affect how well the channels and pumps that sit in the membrane work.

Why Bad Fats And Good Fats Make A Difference

A recent study (1) gives insight into how the lipids in the cell membranes affect how well one particular potassium channel functions. The particular channel the researchers investigated is one of the most studied potassium channels. This channel demonstrates how the function of other channels and pumps also may be affected by the composition of the cell membranes.

The researchers showed that the pore that lets potassium flow through the channel is fine-tuned by the physical characteristics of the lipid in the cell membrane. When the membrane allows protein in the pore of the channel to change more easily, potassium can get through faster.

This study changed two characteristics of the membrane that potassium channels sit in. The two characteristics of the membrane that the researchers changed were the temperature of the membrane, and the type of fats the membrane was made of. Both of these characteristics changed the fluidity of the membrane.

The researchers then determined whether the fluidity of the membrane had any effect on the channel. They measured whether the channel was open, and how much potassium could flow through it.

The researchers found that the more fluid the cell membrane, the more easily the shape of the proteins in the channel could change. The channel was more likely to be open, and was able to conduct more potassium ions through the channel more quickly.

The researchers felt these findings could be generalized to other factors affecting the cell membranes. Other possible factors affecting the fluidity of the membranes were likely to affect the flow of potassium by affecting how easily the channel can change shape.

There have been a great number of epidemiologic studies that show less cardiovascular disease in those who eat less saturated fat. (Arachidic acid is the saturated fat shown above.)  There is also less cardiovascular disease in those who consume more polyunsaturated and monounsaturated fats. It has not been clear how this reduction in cardiovascular disease occurs. However this study shows one of the ways the type of fat eaten affects health.

Fluid Membranes Are Best

Saturated fats make cell membranes stiffer. This is why saturated fats are bad fats. They slow the channels that allow the electric field in cells to change the shape of proteins. The proteins cannot do as much work as they should.

Polyunsaturated fats and monounsaturated fats are good fats because they make the cell membrane more fluid. Thus, the polyunsaturated and monounsaturated fats allow the potassium channels and sodium channels to perform more efficiently. The cell can then maintain the best potassium sodium ratio. The electric field in the cell can change more quickly, allowing proteins in the cell to change shape more easily to do their work.

By maintaining a high potassium sodium ratio in your diet, and by maintaining a high ratio of polyunsaturated and monounsaturated fats to saturated fat in your diet, you can maintain the best environment for cellular function.
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1. Changes in single K(+) channel behavior induced by a lipid phase transition. Seeger HM, Aldrovandi L, Alessandrini A, Facci P. Biophys J. 2010 Dec 1;99(11):3675-83. doi: 10.1016/j.bpj.2010.10.042.

Cellular Function And Potassium Sodium Ratio

What you eat determines how well all the cells in your body function. The potassium sodium ratio is the primary determinant of how well your cells function. This is because the potassium sodium ratio determines the electric field across your cell membranes. This electric field determines the shape and function of all the proteins in your cell. It does this by moving potassium and sodium around to change the electric fields in the cell.
38-PotassiumChannels

Cellular Electric Fields

Although the general concept has been known for quite a while, the details of these electric fields are only now being discovered. Computer simulations and experimental evidence are demonstrating how the electric field created by the potassium sodium ratio and the local electric fields in the proteins work.

Potassium and sodium are moved in and out of the cell by channels and pumps. X-ray crystallography has shown the atomic structure of some channels in their active state. The active state is when the channels are open, and sodium or potassium is moving through them.

However no such views of the atomic structure of channels in their resting state (when they are closed) have been done. And no views of the channels in intermediate states between the active and resting states are available. But multiple computer simulations have been done to show the missing positions of the channels, and to show how the channels function.

How Potassium And Sodium Control Cellular Electric Fields

The potassium and sodium balance in cells is maintained by channels and pumps. They move potassium and sodium from inside to outside and from outside to inside the cell. In doing so they change the electric field of the cell.

This change in the electric field changes the shape of the proteins that are in the field, much like the changing electric field in an electric motor changes the position of the rotor in the motor. Only, the channels and pumps are much faster than an electric motor.

The change in shape of the protein is how the protein functions. The functional result of the changed shape depends on the particular protein. In the case of voltage gated (VG channels) channels the changing shape of proteins results in an alternation of opening and closing the channel.

Voltage gated channels are protein channels through lipid membranes in the cell that let potassium and sodium (and a few other ions) move through them to go from one place to another. They open and close based only on changes in the electric field they sit in. Each type of channel is unique and lets only one type of ion through. Potassium channels let potassium through. Sodium channels let sodium through.

How A Poor Potassium Sodium Ratio Ruins Cellular Function

However if you do not eat enough potassium, or if you eat and retain too much sodium, you will have a less than optimal balance of potassium and sodium inside and outside your cells. This less than optimal balance will result in a less than optimal electric field to motor your cell processes.

If the electric field is stronger (or weaker) than it should be, then when there is a change in the electric field, the channel protein will have to move more (or less) to perform its function. This will result in taking a longer (or shorter) time to perform its function, and will result in incorrect timing of cell processes. This incorrect timing makes it more likely that the cell will function abnormally.

A Close Look At Channels

At present, x-ray crystallography studies of crystallized channels have shown the shape of some open (active) channels. However the shape of a closed channel has not been seen with x-ray crystallography. And none of the intermediate states between open and closed have been seen with x-ray crystallography.

But computer simulations of the resting state of the channel, and of the intermediate states of the channel, have been done. Multiple different methods have been used to create the simulations. And they have all given remarkably similar results. See http://jgp.rupress.org/content/140/6/587/suppl/DC1 for a beautiful video demonstration.

There was a similar situation in the 1980s when MRIs (also known as NMRs), which are also computed simulations, were done to show protein structures. Later x-ray crystallography studies confirmed these computer simulated models.

It is anticipated that when similar x-ray crystallography studies can be done on the channels, a similar confirmation will occur because there is a remarkable similarity in all of the present computer simulations. Thus there is a high probability that the simulations do correspond to what really goes on in the cell.

The Present Study

The present study (1) is a recent review of how these computer simulations were done, and a comparison of the simulations to show how similar their results are. Each simulation was done by a different group of researchers using different computer methods of molecular modeling, and different template x-ray structures. The results of these simulations showed very similar structures of the VSD (voltage sensing domain) of a potassium channel in its resting state.

Several findings have been confirmed by the similarities in the models. The models have shown that the VSD depends upon salt bridges for its shape. Movement of these salt bridges results in a screw-slide movement of the molecules, resulting in the opening and closing of the pore that lets potassium through. The image above shows the open and closed structures of a channel. More is written about salt bridges here and here.

These simulations also showed that VSDs must move through more resting states before activation when they start from a more negative membrane potential. This means that when the potassium sodium balance has changed, there is a change in how the VSDs function. If the electric field is stronger, the proteins in the gate must move more, and take longer to move, between open and closed. If the electric field is weaker, the proteins will have less movement before the pore will open or close.

Several aspects of the models have been confirmed experimentally. Portions of the VSD structure were later confirmed by experimental data. Distances that were predicted between certain atoms in the structure were also confirmed experimentally. The hope is eventually to see in experiments atom-by-atom movement in the structure over time. This would give experimental evidence to confirm the computer simulations.

The Importance Of The Potassium Sodium Ratio

Thus in addition to the interesting findings about how these channels open and close, the simulations also show the importance of the potassium sodium ratio. When the cellular potassium sodium ratio is not optimal, the electric field will not be optimal. And the movement of the protein in the channels will not be optimal, meaning potassium and sodium movement will not be optimal.

When the movement of potassium and sodium through the channels is not optimal, the timing of the all-important changes in electric field will be off. This leads to mistimed cellular processes and abnormal cellular function.

So we have evidence at the atomic level of how important the potassium sodium ratio is. Epidemiologic studies provided the first evidence. Later evidence came from animal and human group studies. Now at the molecular and atomic level, findings are consistent with the importance of the potassium sodium ratio.

If we do not supply too much sodium, and if we supply enough potassium to our body, our body will provide the correct amount to our cells. This will provide an optimal electric field for the very best function of our cells. However if too much sodium or not enough potassium is supplied, the electric fields in our cells will not be at an optimal level. This will result in less than optimal function of our cells, and less than optimal function of ourselves.

This poor cellular function shows up in assorted ways over various periods of time. The most common way it shows up is hypertension and its associated problems of stroke, heart disease, and kidney disease.
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1. An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. Vargas E, Yarov-Yarovoy V, Khalili-Araghi F, Catterall WA, Klein ML, Tarek M, Lindahl E, Schulten K, Perozo E, Bezanilla F, Roux B. J Gen Physiol. 2012 Dec;140(6):587-94. doi: 10.1085/jgp.201210873.

Salt Bridges And Potassium

Potassium in your food matters because your cells need enough of it to function properly. You need enough inside your cells to balance the sodium outside your cells. Your cells do their work by changes in the electrical field produced by moving potassium and sodium around. The changes in the electrical field change the shape of proteins in the cell. When the shapes of proteins change, your cells can extract energy from fuel (food), they can make cell structures, and they can unveil genes and translate genes.

In the last post we discussed how structural changes in the VSD of the gate that opens and closes potassium channels can affect how fast potassium can balance with sodium. Slight changes in the electric field of a cell can cause a difference in the shape of the VSD protein. This change in shape will allow potassium to flow through the channel or will stop it from flowing through.

Protein Molecules’ Shapes

Salt Bridge ChangeThe main determination of the shape of a protein is the sequence of amino acids in the protein. But there are multiple other factors determining the shape. Two major factors are the large cellular electrical field produced by sodium and potassium, and the smaller local electric fields within the protein.

The local electrical fields in a protein come from its amino acids. These fields are determined by the charges on the amino acids in the protein, by the distances between these local charges, and by any ions in the local field.

The force of the larger cellular electric field that the protein sits in is added to the local field forces. Thus this larger electric field influences the strength of local electric field forces, such as hydrogen bonds, salt bridges, electrostatic forces, and other local forces that give rise to the ultimate shape of the protein.

How A Protein Does Its Work

The last post discusses the importance of salt bridges in the function of the VSD. A change in position of six salt bridges in the VSD occurs when there is a change in the electric field across the membrane that the potassium channel sits in. This field change is created by movement of potassium and sodium across the membrane. This causes the protein’s shape to go back and forth, and perform its function of opening and closing gates on the potassium channel.

But you do not need to change multiple salt bridges to affect how a cell functions. A change in just one salt bridge is enough, as discussed in a recent study (1). Especially when the change results in a permanent structural change in a protein.

Severe Bodily Changes From A Salt Bridge Change

This recent study (1) of a salt bridge in an important nuclear protein showed a connection between the severity of a molecular change in the protein and the severity of what happens to a person’s body.

The structural protein (lamin A) that was affected is produced by the LMNA gene. Just like the VSD protein, it is also affected by the charge inside and outside the cell. This protein provides the structure of the nucleus of the cell, and plays a role in the function of the chromosomes. Its structure was changed when a single salt bridge in the protein was changed.

A salt bridge is a very small bond between 2 molecules that is not as strong as a covalent bond. It is composed of a hydrogen bond and an electrostatic bond combined. This post discussed how important salt bridges are in the potassium channels and pumps in cell membranes. Small changes in the electric field that the VSD of a potassium channel sits in changes its six salt bridges and its shape, so channel can do its work.

However a change in the local electric field of just one salt bridge can result in severe changes to a person’s entire body. This study showed that changing one salt bridge can result in massive skeletal abnormalities with an undergrowth of the jaw and collarbones. It can also result in thinning of the bones in the fingers, delayed closure of bony parts, overcrowding of teeth, thinning of the skin, growth retardation, and severe metabolic abnormalities such as lipodystrophy, insulin resistance, diabetes, and hypertriglyceridemia. All of this from a single amino acid change in a protein, resulting in a change in the strength of a salt bridge.

In this particular study, the researchers found 3 different types of changes in a single salt bridge of the protein lamin A. The researchers had 3 patients, each of whom had a change in a single amino acid at position 527 in the protein. This position normally has arginine. By predicting the strength of the salt bridge, they were able to predict how much of a change would occur in a patient’s tissues and organs.

Salt Bridge Changes

In the first case, leucine replaced arginine and led to loss of the salt bridge. Using computer modeling, the researchers predicted severe changes to the patient’s body because the protein structure was destabilized.

In the second patient, histidine replaced arginine, resulting in a weaker salt bridge, but not a loss of the salt bridge, as occurred in the first case. The researchers predicted that the structure of the protein would be destabilized, but less so than with leucine. This led to less severe bodily changes than occurred in the first case.

The third patient had a substitution of arginine with cysteine, which led to a disulfide bridge. This resulted in complete structural change of the protein and led to the most severe bodily change.

Thus with a computer modeling system from multiple bioinformatics sources, the researchers were able to predict the severity of the effect on a person from the severity of the effect on a protein. The effect on the protein came from the physical forces involved in a single salt bridge in a single structural protein. The researchers found that the more severe the change in physical forces between molecules, the more severe the effect on the patient.

Why The Study Is Important

This article shows the importance of the electric field that is created by the potassium and sodium concentrations inside and outside our cells. Small changes in this large electric field change the local fields in our cells’ proteins. These changes back and forth in local electric fields are how our cells do their normal work.

If the large electric field from potassium and sodium is too strong or too weak, the local electric fields may not be able to change adequately. If the local fields cannot change adequately, the protein cannot change shape enough to do its work. When this happens, the cell does not function well, and we do not function well.

Keep your cells functioning well by keeping a good balance of sodium and potassium inside and outside your cells. Eating meals with a high potassium sodium ratio is the best way you can provide your cells with what they need to function well.

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1. A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome. Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M. Eur J Hum Genet. 2012 Nov;20(11):1134-40. doi: 10.1038/ejhg.2012.77. Epub 2012 May 2.

Potassium Channel Gates And Potassium Sodium Ratio

Why is the potassium sodium ratio so important in food? The reason is because it determines the size of the charge differential across cell membranes. And it is the charge differential across cell membranes that determine how well proteins in the membranes, and in the rest of the cell work. If there is too big of a differential, the proteins need a bigger change in charge to change shape and do work in the cell. If there is too little of a difference, the proteins may change shape too quickly or easily.

The last post discussed how changes in electric charges in the cell have optimal rates and an optimal voltage (optimal difference in charge across the membrane) to perform cell functions. So how do these charge changes occur? The charges change by moving ions across the cell membranes. A whole bunch of ions move from inside the cell to outside and others move from outside to inside.

Ion Channels

1r3jThe ions do this movement through channels, which are passive, and pumps, which are active and require energy. Some of the channels only need a change in the electrical field they sit in to open and close. Others need something, such as a protein or calcium, to attach to them in order to change in shape.

These channels that only need a change in charge have an area on them that senses when the electric field changes. This area is called a voltage sensing domain (VSD). The voltage changes when the electric charge inside or outside the cell changes.

The most common example is when a nerve fires. But almost all, if not all, of our cells perform their functions in a similar manner. When the electric charge changes in the cell, events in the cell occur that result in the cell performing its functions.

Each of these VSDs is similar in structure. They are present and retain the same basic structure from the most primitive organism to the most complex beings. When a cell structure is shared so extensively throughout living organisms, it performs an extremely important function. The electric field in the cell is the basis of all the functions in the cell.

Potassium And Sodium Make The Difference

Almost all of the difference in charge across the cell membrane is determined by the potassium and sodium inside and outside the cell. When this charge difference changes, potassium and sodium move. For a nerve cell depolarization, sodium moves inside the cell and potassium outside. When the nerve cell re-polarizes, sodium moves back outside the cell and potassium back inside.

The gate on a channel must open to allow the passage of potassium and sodium. And the gate must close to stop them from passing. The VSD on the channel initiates the opening and closing of the gate. Similar processes in muscle cells, heart cells, hormone cells and other functioning cells are initiated by the movement of potassium and sodium.

How Channels Open And Close

A recent article (1) discusses how these gates open and close. A very important part of how they open and close is based on the electric charge inside and outside the cell. This electric charge difference is known as a voltage potential across the membrane that these channels sit in. In addition to this voltage potential across the membrane there are smaller local electric fields determined in part by the voltage potential across the membrane, and in part by the amino acids in the protein which have charges with effects over shorter distances.

Changing the large electric field that results from this voltage potential affects all the protein molecules sitting in the field. One way the large electric field affects the protein molecule is by affecting the smaller local electric fields in the various parts of the protein. When the local fields change, the protein changes shape.

This article looked at the specific local fields in the VSD to determine how this VSD protein changed shape to open and close the channel gate. There is presently no way to directly measure the inter-atomic forces between the atoms in the gate. Instead, the researchers used a computer simulation based upon many known forces acting at the atomic level. The values of these known atomic forces are collected in multiple databases available to researchers.

The researchers found that the change in electric charge caused a change in the local electric field in salt bridges in the VSD. The change in the local electric field caused salt bridges in the protein in the VSD to rearrange. The rearrangement of the salt bridges caused the channel to close and the reverse resulted in them opening.

Salt Bridge

The salt in a salt bridge does not refer to table salt. It is called a salt bridge because the interaction between 2 ionized sites that sit close to each other in a protein is similar to the interaction between 2 ions of a salt. However the salt bridge has a hydrogen bond as well as an electrostatic interaction.

When the salt bridges rearrange, the protein changes shape, thus opening or closing the gate. This all happens in about 10 microseconds. If the local electric field is not quite right, the timing of the gate opening and closing is not quite right. In this particular study, the researchers found that the depolarization potential had to be complete before a repolarization could occur. If these channels do not function properly, the cell will not function properly.

The post last week showed that there is an optimal voltage and timing for proper function of the sodium potassium pump. The study discussed this week showed that there also is an optimal voltage and timing for proper function of these voltage dependent channels.

You might ask what all this molecular biology has to do with the food I should eat. If your goal is to eat food that will allow the cells in your body to function optimally, you will need to obtain food with enough potassium, and not too much sodium, so that the charge inside and outside your cells is at the proper level. If these charges are not at the proper level, the channels and the pumps inside your cells will work differently. And usually this means that your body will not function as well as it could.
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1. Microscopic origin of gating current fluctuations in a potassium channel voltage sensor. Freites JA, Schow EV, White SH, Tobias DJ. Biophys J. 2012 Jun 6;102(11):L44-6. doi: 10.1016/j.bpj.2012.04.021. Epub 2012 Jun 5.

Cellular Electric Field Effect

It is important to have high potassium foods as the basis of your diet. This is because the potassium sodium ratio of your food determines how well your cells function. Each of your cells needs a lot of potassium inside to balance the sodium outside the cell. This balance creates a difference in electric charge inside and outside the cell. This creates an electric field from the resulting electric potential (voltage) that affects every chemical process inside the cell. If the charge difference is less than optimal, everything the cell does is less than optimal.

An enormous body of scientific work has been done over the years on the details of how this electric field affects your cells. Researchers have done work showing how the field affects the shape of proteins in your cells, and how it affects the speed of chemical processes in your cells.

Electrical potential and field lines between two wires
Cellular Electric Field Effects

The cellular electric field affects the shape of the proteins that send signals. It affects the shape of the proteins that transport ions and molecules. It affects the shape of proteins in the channels that move ions through membranes, and thus affects the movement of those ions. And similarly it affects the pumps that actively move ions and other molecules against their concentration gradient. The ion movement triggers many of the cellular functions.

One very important effect of this cellular electric field is its effect on a critical cellular pump. This particular pump keeps the potassium and sodium balanced inside and outside your cells. It has had various names. Presently the most popular is Na+/K+-ATPase (sodium-potassium adenosine triphosphatase, also known as Na+/K+ pump, sodium-potassium pump, or sodium pump.) The balance of sodium and potassium is so important that estimates have been made that as much as 70% of all your resting energy is spent on maintaining this balance. 20% of your total energy, and up to 70% of the energy used by some cells is spent on this specific pump.

Because this pump is so important, a great deal of research has been devoted to studying it. And because the electric field in the cell has such a major influence on how well the pump works, a great number of studies have been done on the effect of the field on the pump. An early study from 1994 showed how rapidly fluctuating fields affect the sodium potassium pump.

The Study

In this study (1) the researchers isolated the sodium-potassium pumps in cell membranes. They then applied randomly fluctuating electric fields to the pumps. Then they observed the movement of ions across cell membranes. By applying the fields in varying strengths and by varying the frequency that the electric fields changed at, they were able to find the optimal voltage (strength of the field) and the optimal rate of change of the field for maximal movement of the ions.

What this study showed is that there is an optimal rate at which the pumps in the cell membranes can operate. It also showed that this optimal rate is controlled by the voltage across the membrane and by how quickly this voltage changes.

How Cellular Voltage Changes

This optimal voltage is controlled by the ion balance. Ions are charged atoms or polyatoms such as potassium, sodium, calcium, chloride or bicarbonate. The greatest contribution to the voltage is the balance of potassium and sodium inside and outside your cells. Potassium sodium balance is obtained only when you get adequate amounts of potassium and limited amounts of sodium in your diet.

The speed of the voltage change varies for different types of cells. The voltage change results from a change in the electric charge inside and outside the cell. These changes in charge occur when potassium and sodium move back and forth across the cell membrane in channels or pumps. This movement occurs very rapidly – in microseconds. For some channels working properly, over a million ions per second can move through the channel.

What Voltage Changes Do In Cells

This results in cellular proteins changing shape rapidly. When the shape-changing proteins are located in channels and pumps that cross membranes of the cell, ions such as sodium and potassium move through them or are stopped from moving through them, depending on the resulting shape of the proteins. The shape changes occur very rapidly. And thus the voltage changes occur rapidly.

The effect on other proteins in the cell is to change their shapes also. These rapid protein shape changes allow cells to do what they are supposed to do. And when your cells do what they are supposed to do, you can do all the things that you want to do (well, maybe not all the things.)

Now this rapid movement does not mean that faster ion movement is always better for you. But it does mean there is an optimal movement that is determined by the electric field in the cell. And the electric field is determined by the potassium sodium ratio.

A Case Of A Slowed Pump Leading To Longer Life

In certain cells, slowing down some of the cell processes can result in the body functioning better. We saw this in a study that was done on the sodium potassium pump in kidney cells, discussed in this post. When the pump was slowed in these kidney cells, there was less sodium reabsorption. And when less sodium was reabsorbed, there was less excess sodium and less storage of sodium in the body. This resulted in lower blood pressure. And in Sardinians this slower reabsorption of sodium in the kidney resulted in lower blood pressure and longer life, as discussed in this post.

Presently researchers are investigating how the local charges inside the proteins (including the proteins in the pumps and channels) are affected by the overall electric field the protein lies in. And in turn how the change in local charges affects the shape of the protein, how the protein functions and how improper function causes deformities and disease in people. For any given genetic make-up, the electric field is affected by the potassium sodium ratio.
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1. Recognition and processing of randomly fluctuating electric signals by Na,K-ATPase. Xie TD, Marszalek P, Chen YD, Tsong TY. Biophys J. 1994 Sep;67(3):1247-51.

Longevity Gene GWAS

Life span has increased greatly in the last 200 years. But many of the extra years are not lived while in good health. It is been estimated that in modern society only 75 to 80% of life is spent in good health. But there are populations in which older people remain in good health throughout old age. There have been various types of studies to find out whether there is a genetic component to longevity, that is, a longevity gene. Estimates are that approximately 25% of life span variation is due to genetics.

Human genomeA Recent Longevity Gene Study

Despite all this interest, until a recent study there had been only one longevity gene candidate that was found associated with longevity. The present study (1) did a meta-analysis of Genetic-Wide Association Studies (GWAS) for longevity in the older European population. This study found one additional longevity gene (gene associated with longevity).

The researchers felt that this additional longevity gene works by reducing the risk of dying from stroke. They also found it to be associated with lower blood pressure in middle-aged Europeans. These two associations make it very likely that this longevity gene is associated with either sodium or potassium control in the cell. However, the researchers did no studies on the function of the gene.

The longevity gene that this study discovered was not the same gene as the gene that was discussed in the post about the Sardinian centenarians. The report about the Sardinian gene was published in January of this year, and was discovered by a targeted genetic study, not by a GWAS. That report showed that a high percentage of older Sardinians had a gene variant that slowed sodium reabsorption in the kidney.

Too Many Variables

Because the present study involved the general European population, there was a greater mixture of genes and environmental factors than in the Sardinians. This greater mixture makes it very difficult to find genes that contribute to longevity. If there are multiple biochemical pathways with potential longevity genes that are affected by environmental factors, there will be too many variables to account for.

Each potential longevity gene interacts with environmental factors to determine longevity. Because there are so many variants of each of these genes, it would be expected that any particular variant associated with longevity would be rare. This means that none would stand out in a GWAS. More targeted genetic studies in more uniform populations, such as was done in the Sardinian study, are more likely to find genes associated with longevity.

Sardinian Study

In the Sardinian study the Sardinians were relatively uniform in their genetics, having little contribution from genes outside of Sardinia. This genetic isolation has been for several centuries, if not longer. So there has been less chance for a mixture of genes and their variants. The genes that would contribute to longevity would not be as varied, and it would be easier to find contributing variants.

Also the Sardinian study was done in families living as herders in a mountainous area, providing a greater environmental uniformity. Since their physical activity and diet were more uniform than in the general European population, these well known environmental factors would have less influence on differences in longevity.

Approaches other than a Genome-Wide Association Study (GWAS) are needed to find genes associated with longevity. A GWAS involves screening many thousands of genes. A more focused study on some of the areas where there are a great number of centenarians or older individuals, and where there has been little genetic mixture and environmental variation will be more likely to find other genes associated with healthy longevity.

Other Approaches

Because of the high prevalence of hypertension, cardiovascular disease and strokes in old age, and the reduction in function they cause, the genes associated with these diseases would be the best early choices to target in studies looking for longevity genes. As discussed here, many of the genes involved in hypertension are variants involving potassium channels, sodium channels, and calcium channels. In addition to these genes, gene variants in sodium and potassium transporter proteins, and sodium potassium ATPase pump proteins would be good genes to examine.

One of the Blue Zones, made popular by Dan Buettner, would be a good place to start targeted longevity gene studies. Sardinia was one of the Blue Zone areas, and it made possible discovery of a sodium reabsorption gene that may have contributed to the longevity of Sardinians. And some of the other Blue Zones, as well as Sardinia, may provide good populations in which to study these genes.
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1. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, et al. Hum Mol Genet. 2014 Aug 15;23(16):4420-32. doi: 10.1093/hmg/ddu139. Epub 2014 Mar 31.

Salt Sensitivity Test And Hypertension

High potassium foods can help prevent hypertension. With a high potassium to sodium ratio in the diet a great deal of hypertension and the problems associated with hypertension can be prevented. One way to categorize hypertension is to divide it into salt sensitive and salt insensitive hypertension. People with salt sensitive hypertension have a larger elevation of their blood pressure than salt insensitive people when they take in salt. Even when their blood pressure is normal, the salt sensitive people will have increased mortality. And they will have an increase in the problems that are associated with hypertension, such as heart attacks and strokes. It has been estimated that 26% of people with normal blood pressure have salt sensitivity.

Test tubeA Simple Salt Sensitivity Test

It would be helpful to be able to determine who has salt sensitivity so that salt sensitive individuals could have strong advice concerning their salt intake. At the present time, there are a few tests that doctors can run to determine salt sensitivity. However they involve testing that is more complicated than taking a simple blood sample or a simple urine sample. Some researchers recently found a much simpler way to determine salt sensitivity (1). And in doing so, they found a linear relationship between a gene change and salt sensitivity.

The researchers found two different genes in kidney cells that they could test in cells that are shed into urine. These two genes are known to be responsible for a large percentage of sodium reabsorption by the kidney. The genes specifically make proteins that transport sodium in the kidney cell.

First the researchers tested subjects using the usual tests for salt sensitivity. Between one and five years later they checked for the two genes in kidney cells in the urine of these same subjects. They found a linear correlation between changes in these genes and salt sensitivity.

How The Test Helps

This provides a simple test that would allow doctors to advise their patients about salt intake. The standard tests used now are more complicated and involved, and only used for someone with hypertension. They would be hard to justify using for someone with normal blood pressure. And the test may provide the confirmation needed to motivate those salt sensitive patients who otherwise would not reduce their salt intake.

Almost everyone who is healthy would benefit from a high potassium sodium ratio in their diet. But there is some debate about whether increasing potassium, or lowering sodium, or simply improving the ratio is more important. A helpful study these researchers could do would be to study the potassium sodium ratio of the diet along with gene changes in test subjects. It could possibly help resolve the debate by correlating the potassium sodium ratio with blood pressure changes and gene changes.

This type of study would be especially helpful for those patients with so much kidney, heart, and blood pressure problems that they actually may be put at greater risk when put on a very low sodium diet. It may be that these patients would be helped more by increasing their potassium intake, while keeping their sodium intake at a higher level than necessary for healthy people.
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1. A linear relationship between the ex-vivo sodium mediated expression of two sodium regulatory pathways as a surrogate marker of salt sensitivity of blood pressure in exfoliated human renal proximal tubule cells: the virtual renal biopsy. Gildea JJ, Lahiff DT, Van Sciver RE, Weiss RS, Shah N, McGrath HE, Schoeffel CD, Jose PA, Carey RM, Felder RA. Clin Chim Acta. 2013 Jun 5;421:236-42. doi: 10.1016/j.cca.2013.02.021. Epub 2013 Feb 27.

Archives

Recommended

Two excellent books about high potassium foods and blood pressure reduction are available on Amazon. The first is a practical guide to changing your diet to a high potassium foods diet. It is helpful even if you do not have hypertension. The second is a scientific explanation of the diet. It discusses the changes to your body that occur with high potassium foods.

Practical Guide

Scientific Explanation

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