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Orfan Receptor’s «Daddy» Found

It was for a reason that the ancient Greeks said that man was a microcosm. Our body, along with other living organisms, keeps not less mysteries than the distant outskirts of the universe do. Alexander Petrenko, Doctor of Sciences, Head of the Laboratory of Cell Biology of receptors of RAS Institute of Bioorganic Chemistry, told on one such puzzle to understanding of which Russian scientists have approached. These are receptors that can be associated with different states of the body – with the kidney failure, obesity and wanton aggression. And all of them react to an unexpected stimulus – to an increase of the pH in the body.

It is not always easy to assign a biologically active molecule with a specific receptor. For example, the insulin hormone, which is responsible for blood sugar, was discovered nearly a century ago. But receptor protein that reacts to changes in the concentration of the hormone and causes the so-called "cellular response" has been found and studied just over half a century later. And this work is not fully completed.

Immediately after the discovery of insulin receptor two proteins similar to it were discovered, all together, they are called "mini- family of the insulin receptor". The last of them the receptor was discovered which was structurally similar to the insulin receptors, but does not react with the hormone itself. The research group of Alexander Petrenko is engaged in the study of it.

Alexander, tell us about the receptor that you explore.

- This receptor has been found because of its structural similarity to insulin receptors. But it responds neither to insulin nor to similar hormones such as insulin-like growth factor. In fact, this receptor is a something that in the scientific world is called "orphan receptor", that is its activator or as it is known scientifically, ligand was not known. And therefore it is called "insulin receptor- like receptor". In English it sounds like insulin related receptor, or in the Latin abbreviation - IRR, respectively, in the Russian-speaking audience we call it IRR.


What is the essence of your work? What was the original purpose?

- Initially, the goal was to find a natural ligand IRR. I must say that this problem is very interesting, because initially it was assumed that it would be a protein, somehow similar to an important hormone insulin. Preliminary experiments have enabled us to find - quite randomly - the conditions in which the protein could be activated.

Within two years, we have tried to highlight some substance, which disappeared all the time, passed between our fingers. It was found that the essence of the observed activation is the changing of pH.

When people work with cells, they always work, roughly speaking, at neutral pH. It doesn’t occur to anyone to carry out some experiments at other variables of pH. We have managed to do it just by chance, and we watched the reaction of the receptor.

Then, when we began to analyze what happened, we realized that some variability is introduced due to the fact that concentration of carbon dioxide changes in the external environment. And this may be sufficient to change the pH in a weakly alkaline side, and thus to activate the receptor.

And whether there are fundamental differences in the function of insulin receptors and IRR?

- Insulin receptors are present in almost all tissues and almost all cells, but in different amounts. But IRR receptor, as it turns out, is not everywhere.

To date it is clearly shown that the IRR is present in four organs: most of it is in the kidney, slightly smaller is in the pancreas and stomach. Very little is in the nervous system.

If we just look at a range of the fabrics, it becomes clear that this protein really should be in some way connected with the regulation of acid-base balance. Because it is in these bodies where pH of extracellular fluids can vary significantly, both in acidic and alkaline side.

For example, the kidneys are one of two main organs regulating the acid-base balance in the body along with the lungs. Lungs remove the carbon dioxide, i.e., emit the excess acid. Kidneys can dispose of as the excess acid if the lungs do not do in fully due to some reasons, as the excess alkali. The urine pH may vary between 4 and almost 9. And there really should be such proteins that sense pH jumps in these organs.

But what can it do in the brain? This is such an interesting topic that we have got RNF grant to it. And we are trying to understand what the protein can do in the nervous system in vivo.

Previously, for example, there were detected receptors that sense the changes of pH in the acid region in nerve cells. Interestingly, they work as pain sensors and various physical effects sensors. That is, perhaps, lye is also an indicator of some processes, which we do not know yet.

Another important aspect of our research is related to the fact that the IRR is essentially a structural brother of the insulin receptor. Therefore, we may become closer to understanding how the insulin receptor works by exploring the structure of IRR and its transformation upon activation.

How the research of IRR structure will help to understand the mechanism of insulin’s work?

- We carried out work on directed mutagenesis of IRR and watched how its sensitivity to pH chanhed. In the last article we published, we have formulated the concept that there are two main centers of pH-sensitiveness. And the answer in one center increases the likelihood of a response in the other. And here we come to the model that is similar to scissors, has a "lambda form" (in Russian is the letter Л).


Imagine that legs of this letter Л begin to stick together. If there are two spaced centers, one is a little closer to the top, and the other is a little further, then if the convergence occurred on the top, then the convergence on the bottom is facilitated. And positive cooperativity is achieved at the expense of this.

Then, using methods of bioinformatics and computer modeling we have tried to find those amino acids that can be directly involved in the activation. And we continue to work in several directions to study the three-dimensional structure of the IRR and of its change in the activation of the receptor.

Illustrations are provided by the scientific team of A.G.Petrenko


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