Sensory neurons rely on molecular switches, ion channels, to detect extreme cold or heat, mechanical pressure, or harmful chemicals. When a channel opens, admitting the passage of a cation such as Na+, an electrical signal is created and transmitted to the brain. There, the signal is interpreted as pain. This pain pathway, despite its essential service as alarm signal, has a newly discovered flaw: It leaks.
The leak in this case is electrical, a kind of short circuit. When it occurs, an electrical signal does not follow the normal pathway through the central pore of the ion channel. Instead, it navigates an alternative path through the surrounding material. This electrical leak activates the pain nerves and actually intensifies the sensation of pain.
This alternative pain pathway was discovered by a team of scientists at KU Leuven who were investigating potential pain killers. To their surprise, they found that several candidate pain killers enhanced sensations of pain. Their work, detailed in an article published January 5 in Nature Chemical Biology, focused on a particular transient receptor potential (TRP) channel, TRPM3.
TRP channels are tetramers, and it is generally accepted that binding of ligands causes the opening of a single central cation-conducting pore. TRPM3 is a TRP channel that can be gated by combined application of endogenous neurosteroids and exogenous chemicals such as clotrimazole or several structurally related drugs.
TRPM3, as the investigators knew from previous work, acts as a molecular fire detector. This ion channel detects heat and the hormone pregnenolone sulfate, a precursor to the sex hormones estrogen and testosterone and a trigger for pain and inflammation.
The present work (“Opening of an alternative ion permeation pathway in a nociceptor TRP channel”) started as an investigation of TRPM3 inhibitors that were meant as pain killers. Instead, the work revealed that TRPM3 had a second permeation pathway.
According to the investigators, led by Thomas Voets, Ph.D., and Joris Vriens, Ph.D., “This alternative pathway is preserved following desensitization, blockade, mutagenesis, and chemical modification of the central pore and enables massive Na+ influx at negative voltages. Opening of this alternative pathway can enhance excitation of sensory neurons and thereby exacerbate TRPM3-dependent pain.”
Ordinarily, closing an ion channel prevents electrical signals from reaching the brain. Yet with some TRPM3 inhibitors a blocked channel enhanced pain, thanks to the electrical leak.
Dr. Voets speculates that this electrical leak may explain the pain-enhancing side effects of some drugs, such as clotrimazole, a common remedy for yeast infections that often causes unpleasant side effects such as irritation and burning sensations. “It is striking that short circuits in the ion channel occur only at high hormone levels. This could explain why some patients experience these side effects while others do not,” added Dr. Voets.
The researchers concluded their article by expressing the hope that their work will contribute to the pain therapeutics: “Our findings indicate that a single sensory TRP channel can encompass two distinct ionotropic chemoreceptors, which may have important ramifications for TRP channel function and pharmacology.”