Unique Interweaved Microtubule Scaffold Mediates Osmosensory Transduction via Physical Interaction with TRPV1

The electrical activity of mammalian osmosensory neurons (ONs) is increased by plasma hypertonicity to command thirst, antidiuretic hormone release, and increased sympathetic tone during dehydration. Osmosensory transduction is a mechanical process whereby decreases in cell volume cause the activation of transient receptor potential vanilloid type-1 (TRPV1) channels to induce depolarization and increase spiking activity in ONs. However, it is not known how cell shrinking is mechanically coupled to channel activation. Using superresolution imaging, we found that ONs are endowed with a uniquely interweaved scaffold of microtubules throughout their somata. Microtubules physically interact with the C terminus of TRPV1 at the cell surface and provide a pushing force that drives channels activation during shrinking. Moreover, we found that changes in the density of these interactions can bidirectionally modulate osmosensory gain. Microtubules are thus an essential component of the vital neuronal mechanotransduction apparatus that allows the brain to monitor and correct body hydration. •Superresolution imaging reveals microtubule scaffold required for mechanotransduction•A microtubule-TRPV1 interaction is required for central osmosensation•Microtubules provide pushing force mediating mechanical activation of TRPV1•Osmosensory gain is regulated by the density of tubulin-TRPV1 sites Body fluid homeostasis is mediated by central osmosensory neurons that are excited by plasma hypertonicity. Prager-Khoutorsky et al. demonstrate that these neurons feature a unique microtubule scaffold that interacts with TRPV1 channels and mediates their mechanical activation during cell shrinking.