Researchers of the Max Delbrόck Center for Molecular Medicine (MDC) Berlin-Buch have found out why the African naked mole-rat (Heterocephalus glaber), one of the world's most unusual mammals, feels no pain when exposed to acid. African naked mole-rats live densely packed in narrow dark burrows where ambient carbon dioxide (CO2) levels are very high. In body tissues, CO2 is converted into acid, which continuously activates pain sensors. However, naked mole-rats are an exception: they have an altered ion channel in their pain receptors that is inactivated by acid and makes the animals insensitive to this type of pain. Dr. Ewan St. John Smith and Professor Gary Lewin conclude that this pain insensitivity is due to the African mole-rats' adaptation to their extreme habitat over the course of evolution.
The Nav1.7 sodium ion channel plays a key role in the transmission of painful stimuli to the brain. It triggers a nerve impulse (action potential) in the pain receptors -- sensory nerve cells, the endings of which are found in the skin and which transmit pain signals to the brain. Dentists already use sodium ion channel blockers in the form of local anesthetics, but these target all sodium ion channels they come into contact with, not just the Nav1.7 ion channel. People with defective Nav1.7 ion channels due to a genetic mutation feel no pain, but for them, pain insensitivity is not at all an advantage: minor injuries or infections can go unnoticed, often with serious consequences.
However, this is different for the African naked mole-rat. For these animals, pain insensitivity to acid is evidently a survival advantage. The air in the burrows has such high CO2 levels that humans or other mammals could hardly survive in such an environment. Normally, high CO2 levels and acid cause painful burns and trigger inflammation in all mammals, including humans. Thus, the tissue of patients with inflammatory joint diseases such as rheumatism contains high concentrations of acid. These high acid levels in the tissue activate the pain sensors.
Naked mole-rats also have pain sensors. In a previous study, the research group of Professor Lewin already showed that naked mole-rats are just as sensitive to heat and pressure as mice are. In contrast, they do not feel any pain when they are exposed to acid. Moreover, as Dr. St. John Smith and Professor Lewin report in the American journal Science, naked mole-rats also have the Nav1.7 ion channel like other mammals, including mice and humans. The researchers therefore investigated the function of this ion channel in naked mole-rat and in mouse sensory nerves to determine whether there is a difference between the two species in the function of this ion channel.
In the present study the researchers showed that the NaV1.7 ion channel of the naked mole-rat does in fact differ in structure from that of the mouse or of humans. Ion channels are proteins composed of amino acids, the blueprint of which is coded by the genes. In the NaV1.7 ion channel of the naked mole-rat, three amino acid building blocks are different from those in all other mammals. These three altered protein subunits lead to profound impairment or blockage of the naked mole-rat ion channel by acid. This phenomenon can also be observed in the Nav1.7 ion channel of mice and humans, but it is so weak that the transmission of pain signals is hardly disturbed.
In the naked mole-rat, however, this mutated ion channel is sufficient to inhibit signal transduction. The reason for the mutation in the ion channel, according to the researchers, is that naked mole-rats have adapted over the course of evolution to the high CO2 levels in the air and thus have become insensitive to pain induced by acid. This is also the case when in the nerve cells of the naked mole-rats other ion channels are activated by acid stimuli that would normally activate pain receptors.
Cave-roosting microbats and tree-roosting megabats
In a number of mammals the structure of the gene for the Nav1.7 ion channel has been decoded. These include the cave-roosting microbat (Myotis lucifigus), a bat that lives in a similar habitat and exhibits a similar gene variant. In contrast, another species, the tree-roosting megabat (Pteropus vampyrus), also lives in large colonies like the mole-rat and the cave-roosting microbat, but it is not under any CO2 pressure. According to the researchers, this suggests that under similar environmental conditions in the course of evolution, unrelated species develop similar traits. For the African naked mole-rat, and perhaps for the cave-roosting microbat, this means that CO2 and acid cannot induce pain.
Significance for patients with inflammatory diseases?
What do the findings of the MDC researchers mean for patients with inflammatory diseases, in whom this ion channel is continuously activated? According to Professor Lewin, the pharmaceutical industry is already working to develop small molecules that will block this ion channel. The findings from the laboratory of Professor Lewin -- that three altered protein subunits inhibit the signal transduction of Nav1.7 -- may aid the development of small molecules that specifically block this mutated ion channel.
- E. S. J. Smith, D. Omerbasic, S. G. Lechner, G. Anirudhan, L. Lapatsina, G. R. Lewin. The Molecular Basis of Acid Insensitivity in the African Naked Mole-Rat. Science, 2011; 334 (6062): 1557 DOI: 10.1126/science.1213760
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