A pentameric TRPV3 channel with a dilated pore.

Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive drug targets1-5. More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers4. Despite this wealth of structures, many aspects concerning TRPV channels remain poorly understood, including the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification6,7. Here, we used high-speed atomic force microscopy (HS-AFM) to analyse membrane-embedded TRPV3 at the single-molecule level and discovered a pentameric state. HS-AFM dynamic imaging revealed transience and reversibility of the pentamer in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation. On the basis of these findings, we designed a protein production and data analysis pipeline that resulted in a cryogenic-electron microscopy structure of the TRPV3 pentamer, showing an enlarged pore compared to the tetramer. The slow kinetics to enter and exit the pentameric state, the increased pentamer formation upon DPBA addition and the enlarged pore indicate that the pentamer represents the structural correlate of pore dilation. We thus show membrane diffusive protomer exchange as an additional mechanism for structural changes and conformational variability. Overall, we provide structural evidence for a non-canonical pentameric TRP-channel assembly, laying the foundation for new directions in TRP channel research.

Is there hemispheric specialization in the chronic pain brain?

Organismal bilateral symmetry is associated with near-identical halves of the central nervous system, with certain functions displaying specialization through one brain hemisphere. The processing of pain in the brain as well as brain plasticity in the context of painful injuries have garnered much attention in recent decades. Noninvasive brain imaging studies in pain-free human subjects have identified multiple brain regions that are linked to the sensory and affective components of pain. Longlasting adaptations in brains of chronic pain sufferers have likewise been described, suggesting a mechanism for pain chronification. Invasive molecular and biochemical studies in animal models have expanded on these findings, with added emphasis on the role of specific genes and molecules involved. To date, the extent of hemispheric asymmetry in the context of pain is not well-understood. This topical review evaluates the evidence of hemispheric specialization observed in humans and rodent models of pain and compares it to findings where such asymmetry is absent. Our review shows conflicting information regarding the existence of pain-related asymmetry, and if so, the side to which it can be localized. This could be due to the heterogeneity of pain processing pathways, heterogeneity in study parameters, as well as differences in data reporting. With the advent of progressively sophisticated non-invasive tools that can be used in human subjects, in addition to more precise methods to visualize and control specific brain regions or neuronal ensembles in animal models, we predict that the next few decades will witness a better understanding of the supraspinal control and processing of chronic pain, including the role of each of its hemispheres.