This new understanding could lead to potential advances in pain therapy, the researchers said. Moreover, the scientists envision that their method may be potentially useful in studying the activation mechanism of other drugs and proteins.
"Because our ability to sense temperature is closely linked to our ability to sense pain, it is not surprising that the misregulation of temperature-activated ion channels can result in chronic pain syndromes," said Ardem Patapoutian, associate professor at Scripps Research and member of GNF, who directed the research. "In fact, some of these ion channels are considered targets to treat chronic inflammatory and neuropathic pain indications. Understanding how small molecules such as menthol affect the function of these proteins could be crucial in designing future drugs that can either activate or block them."
The study was released in an advanced online version by the journal Nature Neuroscience.
Utilizing a novel mutagenesis and high-throughput screening approach, the study assayed 14,000 TRPM8 mutants to find mutants that were not enhanced by menthol but were otherwise functioning normally. The scientists' analysis pinpointed a potential interaction site for menthol, as well as a site that translates binding information to ion channel activity.
Ion channels are proteins found in the cell membrane that can form a tunnel or channel that allows specific ions to move across the membrane. When activated, the channel opens, allowing an influx of calcium ions into the axon, an electrical signal that alerts the neuron, which relays the message to the brain.