Scientists Uncover Shared Activation Mechanism for Heat and Chemical Sensing in Pain Receptor

Structural Breakthrough in Pain Receptor Understanding

Scientists have made significant progress in understanding how the body’s pain detection system responds to multiple stimuli, according to recent research published in Nature Structural & Molecular Biology. The study provides the first detailed structural analysis of how TRPM3, a key pain receptor, is activated by both temperature changes and chemical compounds through a shared mechanism.

Structural Breakthrough in Pain Receptor Understanding
Multi-Stimuli Investigation Approach
Ligand Binding Reveals Activation Pathway
Conformational Diversity and Dynamic Equilibrium
Heat Activation Shares Common Mechanism
Unified Activation Pathway Identified
Implications for Pain Treatment Development

Multi-Stimuli Investigation Approach

Researchers reportedly used rabbit TRPM3 as their primary study subject due to its exceptional stability following thermal exposure, a common challenge when working with purified proteins. Sources indicate the rabbit version shares over 98% sequence identity with human and mouse variants, making the findings highly relevant to human biology. The team employed cryo-electron microscopy to capture high-resolution structures of the receptor under various conditions, achieving resolutions as fine as 2.6 Ångström.

Electrophysiological experiments confirmed the receptor’s sensitivity to both temperature and chemicals, analysts suggest. Heating or exposure to the endogenous agonist pregnenolone sulfate induced reversible activation, while the superagonist CIM0216 elicited even stronger responses. The research also examined how the anticonvulsant primidone suppresses TRPM3 activity, potentially explaining its pain-relief properties.

Ligand Binding Reveals Activation Pathway

The report states that researchers first used CIM0216 to understand structural changes during activation, determining its binding site within the S1-S4 domain of the transmembrane region. The T-shaped molecule engages residues on multiple helices through both hydrophobic and hydrophilic contacts, forcing conformational changes that propagate throughout the protein structure.

According to the analysis, CIM0216 binding causes the TRP helix to elevate toward the extracellular side and rotate along the pore axis, while also shifting the S4 helix and S4-S5 linker. These regions are described as critical gating elements in the TRP superfamily that mediate communication between different protein domains.

Conformational Diversity and Dynamic Equilibrium

Structural analysis revealed that TRPM3 exists in multiple conformational states simultaneously, even when bound to a superagonist. Researchers identified six distinct tetrameric conformations with varying combinations of resting and activated subunits. The findings suggest that TRPM3 channels naturally sample both resting and activated conformations, existing in a dynamic equilibrium that external stimuli can influence.

Sources indicate that tetramers with three or four activated subunits were predominant when bound to CIM0216, while those with fewer activated subunits were less common. This distribution pattern provides insights into how the channel achieves graded responses to different stimulus intensities.

Heat Activation Shares Common Mechanism

When investigating temperature-dependent activation, researchers determined structures at both 18°C and 37°C. The report states that heat markedly altered the conformational distribution: at 18°C, resting conformations dominated (84%), while at 37°C the proportion of activated conformations increased to 40%. This temperature-dependent shift supports what analysts describe as a “conformational selection model,” where proteins intrinsically sample different states and external stimuli bias the equilibrium.

Notably, the proportion of tetramers with three or four activated subunits increased 14-fold at 37°C compared to 18°C, though this remained lower than the 83% observed with CIM0216-bound TRPM3. This difference aligns with functional data showing that maximal heat-induced TRPM3 activity occurs at temperatures higher than 37°C.

Unified Activation Pathway Identified

The most significant finding, according to reports, is that both heat-induced and agonist-induced activation share a common structural transition in the intracellular domain. Specifically, the MHR1/2 domain dissociates from the rib helix during activation, regardless of whether the stimulus is temperature or chemical.

Researchers tested this mechanism by creating mutants designed to weaken the interaction between these domains. The report states these mutants not only produced larger heat-induced currents but also demonstrated dramatically enhanced sensitivity to agonists—up to 13-fold higher sensitivity to the endogenous agonist PregS and threefold higher sensitivity to CIM0216.

Implications for Pain Treatment Development

The converged activation mechanism provides new understanding of how diverse stimuli can activate the same receptor through shared structural pathways. According to analysts, this knowledge could inform the development of more targeted pain treatments that modulate TRPM3 activity. The structural insights into how primidone inhibits TRPM3 may also help optimize existing medications for better pain management.

The research demonstrates that the inherent structural dynamics of TRPM3 enable natural sampling of both resting and activated states, providing flexibility for responding to diverse activation stimuli. External stimuli, whether thermal or chemical, reportedly bias this equilibrium toward the activated state through a common structural transition centered in the intracellular domain.

References

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