Alkalinity And Kir

The high potassium foods diet is a diet that is high in potassium, low in sodium and produces an alkaline urine. It is a diet that is based on principles that can be deduced from multiple studies of indigenous peoples, modern populations, and the variations in diet among all these peoples. It also is backed by a great deal of basic science research.

Central to the basic science is the electric field of the cell, and the local fields within molecules that determine their structure and activity. The electric field of the cell is determined by the potassium and sodium inside and outside the cell. Much of the structure and activity of the molecules in the cell is determined by the action of the potassium channels, sodium channels, ATP and multiple transporters of molecules within the cell.

A large part of the work that researchers are doing at the present time is to determine how these channels, pumps, and transporters work. Among the potassium channels there are 4 main classes of channels. The classification is based on the major way that the potassium channel works.

Kir Channels (Inwardly Rectifying Potassium Channels)

PDB 1p7b EBI
Inwardly rectifying potassium channel

Most potassium channels move potassium ions from inside to outside the cell. But one class of channels moves potassium from outside to inside the cell. These are named Kir channels and the class of channel is called inwardly rectifying channels.

These channels bring potassium from outside the cell to inside the cell to stabilize the resting potential of the cell membrane. They provide a balancing current to the current of the dominant potassium channels that send potassium in the opposite direction. They are most active after the membrane has depolarized and is returning to a resting potential.

These channels are found in multiple types of cells. In heart cells they help to control the heart rhythm. In the kidney cells they are involved with potassium excretion and resorption. In the pancreas they help with insulin release. In nerve cells they aid the return to inactivity after the nerve has fired. In cells that line blood vessels the loss of the channels' function is one of the earliest signs of atherosclerosis.

In the kidney principal cells these channels are the ROMK channels. They are the channels that work in concert with sodium-potassium ATPase (sodium pump). The majority of potassium excretion for those on a high potassium foods diet is through other potassium channels. But the ROMK channels are an important part of the process. The process of how the kidneys can excrete large amounts of potassium and recycle sodium was discussed in this post here.

Kir Characteristics

The first of two important characteristics of the Kir channels is that they are all affected by PIP2. PIP2 must dock to the channel before the channel activates. The second important characteristic is that many of the Kir channels are pH sensitive. The pH sensitivity of these channels is especially interesting, since the kidneys can excrete so much more potassium when the urine is alkaline (a high pH).

The researchers in the publication (1) to be discussed today determined how these Kir channels close. They determined what change in structure of the channel occurred when the closing of the channel was related to the action of PIP2, or to the action of a change in pH, or to a change in potassium concentration. All three of these stimuli caused the same change in structure of the channel.

These Kir channels have three structural elements in common. The first is a selectivity filter outside the cell membrane that can accept potassium ions and exclude sodium ions. The second is a pore that runs through the cell membrane. The pore is made of two types of transmembrane (TM) helices. And the third element is a portion inside the cell membrane called the cytoplasmic domain.

The 2 TM helices cross each other at the base of the channel. As one type of TM helix (TM1) slides during the closing action, its lysine approaches an alanine on the other helix (TM2). This is the location where the pore closes. The researchers found that when these two amino acids are opposite each other, the distance between them allows a hydrogen bond to form between the two and close off the pore. This prevents potassium from passing through the channel. The researchers found that this model correlated very well with the measured PIP2 activation rate.

Why Alkalinity Is Important

The researchers then repeated this procedure varying the pH. They found a strong correlation of this action with pH sensitivity. A low pH (acid) closed the channel. The channel opened at an alkaline pH (8.0). Although there were differences in the closing caused by the action of PIP2 and by the action of pH, the researchers were able to correlate pH with the hydrogen bond model by measuring the speed of activation.

The researchers found that PIP2, pH, and potassium concentration outside the cell all worked through the same mechanism to close the channel. All three conditions closed the channel by forming a hydrogen bond between lysine and alanine. The researchers did this by doing computer simulations with different amino acids at the lysine position in TM1, which was known previously to be the site of pH sensitivity.

By substituting amino acids for the lysine they were able to determine how quickly the shape changed, and to determine the distance between the substitute amino acid and alanine in the opposite helix. The researchers then compared this to laboratory experiments in which they changed PIP2, pH, and extracellular potassium concentration. They found a high correlation between the laboratory results and the computer results. If the distance between the amino acid substituting for lysine and the amino acid (alanine) that the substitute closed against had the distance of a hydrogen bond, the pore closed. If the distance between the amino acids was larger than a hydrogen bond, the pore did not close.

Thus the researchers showed how pH affects the closing of these channels. A hydrogen bond closed the channel. It required enough hydrogen ions (a low enough pH), and the right amino acids in the right positions in the channel for closure to occur. This model explains why when the pH is alkaline, the channel stays open.

If this model is true for other channels emptying potassium into the urine, it adds another piece to the puzzle of how an alkaline urine combines with a high potassium sodium ratio in the diet to provide cellular balance.
1. H bonding at the helix-bundle crossing controls gating in Kir potassium channels. Rapedius M, Fowler PW, Shang L, Sansom MS, Tucker SJ, Baukrowitz T. Neuron. 2007 Aug 16;55(4):602-14.

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