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 have an altered ion channel in their pain receptors that is inactivated by acid and makes the animals insensitive to this type of pain. Doctor 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 anaesthetics, 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.
In the study, the researchers showed that the NaV1.7 ion channel of the naked mole-rat does 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.
What do the findings of the researchers mean for patients with inflammatory diseases, in whom this ion channel is continuously activated? According to Lewin, the pharmaceutical industry is already working to develop small molecules that will block this ion channel. The findings – 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.
MEDICA.de; Source: Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin-Buch