Unraveling the Mystery of Body Temperature! The Mechanism of "Too Hot" Uncovered at the Molecular Level

Introduction: The Black Box of Temperature Sensation Opens

The split-second decision we make to withdraw our hand when we feel heat is managed by molecular machinery within our skin and nerves. One of the key players, "TRPM3," detects "heat" and converts it into an alarm of pain. This fundamental mechanism has been depicted at the atomic level by combining "molecular snapshots" from cryo-electron microscopy (cryo-EM) with electrophysiology. The study was published on October 24, 2025, in Nature Structural & Molecular Biology. It was decisively shown that the detection of heat is primarily managed by the **intracellular domain (ICD) of the protein**, rather than the outside of the membrane.Nature

What Was Discovered: The Tetrameric Switch That Flips Internally

Although TRPM3 is a channel embedded in the membrane, the analysis clearly demonstrated that the "activation points" for heat and chemical agonists (CIM0216) are located in the channel's intracellular domain (ICD). When the ICD, composed of four subunits, is tightly interlocked, it is inactive. However, when heat rises or an agonist enters, the binding loosens, the structure slides, and the channel opens, allowing ions to flow. This behavior of "pressing the same internal switch" occurs convergently with both temperature and chemicals, as confirmed by both structural and current recordings.Nature

Furthermore, the antiepileptic drug primidone binds to the same site (S1–S4 region) as CIM0216 but exhibits antagonistic action by "biting" into the channel's activation and blocking it. The correspondence between structure and function also provided the spatial basis for inhibition. Nature

How It Was Discovered: The "Dual-Wielding" of Cryo-EM × Electrophysiology

The research team overcame the classical challenge of not being able to directly "observe" heat with two strategies. First, they captured the structure of TRPM3 activated by the super-potent agonist CIM0216 and inactivated by primidone using cryo-EM, identifying movable sites from the differences between the two. Second, they compared structures at low and high temperatures, confirming that rearrangements within the ICD occur commonly with both heat and chemicals. As a supplementary line, they tracked current behavior using whole-cell patch clamp, supporting that structural differences manifest as functional differences. Nature

Differences from Existing Views: Not Just TRPV1, A Pluralistic View of Temperature Reception

While TRPV1, known as the "spicy receptor," has been considered central to heat pain perception, TRPM3 is also strongly activated around 40–45°C and has been suggested to be an important molecule in pain circuits. This paper provides a new coherent model for the molecular physiology of temperature sensation by clarifying the image of TRPM3 as an **"internal temperature sensor"** that responds to temperature changes through internal folding/connection dynamics.Nature

Medical Implications: Applications in Non-Addictive Pain Relief and Neurological Disorders

TRPM3 is associated with phenotypes such as pain, inflammation, female migraines, and epilepsy, and the finding that temperature and chemicals converge on the same internal switch directly connects to the rational design of selective modulators. Notably, the clinical drug primidone has been repeatedly shown in preclinical studies to strongly inhibit TRPM3 and potentially reduce thermal pain and inflammatory hypersensitivity. Optimization of structure-based inhibitors/activators could become a promising route for novel non-opioid analgesics.PMC

Limitations and Next Steps

• Species Differences and Splice Variants: This study primarily used rabbit TRPM3, but further verification is needed to determine how consistent the ICD dynamics are across human isoforms.Nature

• In Vivo Context: The impact of membrane potential, lipid environment, and cofactors unique to in vivo on opening probability requires further verification with integrated methods.Nature

• Refinement of Pharmacology: In addition to CIM0216 and primidone, the exploration of compounds with high selectivity and safety and the acceleration of structure-based drug design are anticipated.Nature

SNS Reactions: Interest Concentrated on Structural "Appeal" and Pain Relief Expectations

The Altmetric score immediately after the paper's release was 35, a promising start for basic research on molecular structures. Attention was drawn to the completeness of the cryo-EM illustrations and the path towards pain relief alternatives to opioids. The research team also announced "Published in NSMB" on the same day, promoting dissemination within the community. Additionally, since the beginning of the year, the bioRxiv version had been shared and mentioned within the biophysics community. Overall, there is a sense of progress in discussions moving from the "TRPV1-centric" view to a pluralistic understanding of temperature reception.dululabs.com

Points for Practitioners (Research, Drug Development, Media)

• Drug Development: Targeting the dynamic hotspots of the ICD enables structure-driven optimization for both agonists and antagonists. The structural information of the existing drug primidone provides a good starting point for repurposing/new drug design.Nature

• Neuroscience: The unified view that inputs from temperature and chemicals converge on the same internal switch aids in simplifying pain circuit models and redesigning evaluations of contributions by temperature range (e.g., 40–45°C range).Nature

• Science Communication: The reversed perspective of "sensing temperature not outside the skin but internally" is easily conveyed to the general public. This framing has been reported by Phys.org and university public relations. news.northwestern.edu