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Short circuit to pain: TRP channel alternative pathway
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Researchers from KU Leuven in Belgium have identified a ‘short-circuit’ mechanism in chemosensors called transient receptor potential (TRP) channels that can paradoxically lead to increased pain in response to candidate painkillers targeting these channels. The work, published online in last week’s Nature Chemical Biology focused on one member of the TRP family called TRPM3.

Pain provides with a vital ‘warning’ system alerting us to the dangers of, for example, extreme heat or cold. A network of sensory nerves, for example in the skin and mucosa, relays pain signals from around the body to the brain. Around these nerves are ion channels such as the TRP family. The TRP family act as primary chemosensors. Upon binding of a ligand, a cation conducting pore opens in the middle of the TRP channel. This results in a tiny electrical signal which when it is transmitted to the brain is interpreted as pain. The Belgian group’s work involved study of candidate painkillers which would target the TRPM3. This channel detects heat and the hormone pregnenolone sulfate, a pain and inflammation trigger. TRPM3 can be gated by combinding drugs such as endogenous neurosteroids and exogenous chemicals such as clotrimazole.

In an in vivo mouse model, the Belgian study found that an alternative pathway was mediated via TRPM3 when channels were closed by a number of different mechanisms including desensitization, blockade, mutagenesis and chemical modification of the central pore. This pathway therefore did not depend on an open ion channel. Instead, it involved a ‘short circuit’ whereby the stimulus found a different route; rather than using the central pore, it carved a path through the surrounding material and activated the nearby pain nerves, sending a pain signal to the brain. The overall result was to exacerbate TRPM3-dependent pain. The researchers maintain that this mechanism may explain the pain-enhancing side effects of drugs such as clotrimazole and thy hope that it will shed new light on TRP channel function and pharmacology.

Sources

Vriens, J., Held, K., Janssens, A., Tóth, B., Kerselaers, S., Nilius, B., Vennekens, R., & Voets, T., 2014, 'Opening of an alternative ion permeation pathway in a nociceptor TRP channel', Nature Chemical Biology, viewed 14 January 2014

Press release: http://www.kuleuven.be/english/news/shor...ifies-pain
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