10 hours Ago
Sensory neurons that respond to temperature, touch and pain have ways of adapting to repeated stimuli that can change how a body experiences those sensations. In a recent paper published in the Proceedings of the National Academy of Sciences , Thomas Jefferson University researchers describe a specific molecular change that accounts for this altered neuronal activity and, in turn, the strength of pain sensation. Neurons send signals via action potentials, which involves a rapid exchange of ions across tiny conduits in the membrane called ion channels .
Ion channels also work to quickly end this exchange. This electrical discharge is responsible for the remarkable speed and versatility of signaling in our nervous system. With repeated firing, action potentials get progressively longer (they're still fast, but not as fast).
Neuroscientists have observed this phenomenon for years, but the mechanism was poorly understood. The new study clarifies: A molecular change in a specific potassium ion channel speeds up their closing and lengthens the action potential. "This potassium channel is a major player in ending action potentials, but its function depends on a critical chemical modification," says neuroscientist and senior author of the study, Manuel Covarrubias, MD, Ph.
D. Namely, a group of chemicals called phosphate groups are added to the potassium channel to make it more efficient at terminating action potentials. When the channel doesn't have enough of these chemicals, it doesn't close as easily, and sensory stimulation that causes repeated firing makes action potentials longer and increases pain.
Through painstaking experimentation, Dr. Covarrubias and his research team, including MD/Ph.D.
student Tyler Alexander, have ascertained the specific phosphate tagging sites on the particular potassium channel that leads to longer action potentials . Now there's a target for potential therapeutic intervention. In short, a treatment that boosts potassium channel function could alleviate clinically relevant pain conditions.
This work is a stellar example of how basic research in molecular detail opens the door to potentially novel approaches in clinical translation. More information: Tyler D. Alexander et al, Molecular mechanism governing the plasticity of use-dependent spike broadening in dorsal root ganglion neurons, Proceedings of the National Academy of Sciences (2024).
DOI: 10.1073/pnas.2411033121.
