TRPV4: Mechanosensitivity and Skeletal Dysplasia

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Unlike vision, smell, and tastes, the molecular mechanisms of hearing, touch, and blood- pressure or systemic-osmolarity sensing are unknown. How ion channels receive mechanical forces remain obscure, except for bacterial channels MscL, MscS. We are using the rat TRP channel V4 subtype, to help fill this knowledge gap. We have now shown TRPV4's direct response to membrane stretch under Xenopus oocyte patch clamp. We have also developed yeast as a new arena to dissect TRPV4. Our work challenges a previous TRPV4's osmotic-gating model. We plan to define the force-sensing domain within TRPV4, using strategic peptide insertions and chimeras. 2008-11 found TRPV4 gain-of-function mutations to cause two sets of human diseases: skeletal dysplasia (SD) and adult peripheral neuropathy. We examined 14 SD alleles and found the level of increased basal TRPV4 activity parallels the severity of the SD disease. Besides understanding the working of the wild-type TRPV4 channels, we now plan to examine 17 mutations in the ankyrin-repeat domain (ARD), of which crystal structure is known. This work aims towards understanding how ARD mutations can lead to two disparate diseases. In collaboration, we will also use trpV4-/- knock-out mice to test the role of TRPV4 in fracture healing.