Decoding the Mechanism of Pain: The Molecular Switch to Prevent Chronic Pain Overdrive - Here Lies the "Emergency Stop Button" for Pain

The molecular mechanism by which the pain receptor channel TRPA1 rapidly inactivates (desensitizes) after calcium influx has been shown to involve calmodulin (CaM) binding primarily with its C-lobe to a novel binding site on the distal C-terminus (DCTCaMBE), playing a role in "closing" the channel. Disruption of this binding leads to overactivation and delayed inactivation, which can be partially rescued by an increase in extracellular Ca²⁺, suggesting that Ca²⁺/CaM acts as an auxiliary subunit of TRPA1, promoting blockade through remote allostery. This represents the "switch" that prevents the runaway of chronic pain and provides a concrete target for novel analgesic drug development aimed at the binding interface. However, this is primarily basic research centered on cell systems, and challenges remain in causal verification in primary sensory neurons and animal models, as well as pharmacological selectivity due to the ubiquitous nature of CaM. University news and Phys.org have released explanations for the general public, and the study garnered attention on professional social media from the preprint stage, becoming a topic of discussion again after peer-reviewed publication.