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• W2064595024 abstract "Mutations in many genes encoding proteins, such as the two transmembrane domain-containing protein TMIE, cause heritible deafness. Sound and acceleration produce waves in the lymph of the inner ear and vestibular appartus that deflect the stair-stepped stereociliary bundle of hair cells. Deflection toward the tallest cilium induces opening of a Ca 2+ -permeable mechanotransduction channel leading to an electrical current that is transmitted to the brain. The exact identity of the pore-forming subunit of this channel is unknown (see Liedtke). However, filaments (known as tip links) formed by the cadherins PCDH15 (on the shorter cilium) and CDH23 (on the taller cilium) connent cilia together and are required for Ca 2+ entry in response to deflection. Ca 2+ entry occurs near the base of the tip link on the shorter cilium. In addition, the tetraspannin protein LHFPL5 interacts with PCDH15 and may allosterically regulate the mechanotransduction channel. Using a yeast two-hybrid approach, Zhao et al . discovered that PCDH15 and LHFPL5 can bind to TMIE. Experiments in cultured human embryonic kidney (HEK) 293T cells confirmed this interaction and revealed that TMIE, PCDH15, and LHFPL5 form a ternary complex. TMIE localized to the tip links of cilia in inner ear hair cells of mice. Mice with null alleles of Tmie or with conditional knockout of Tmie in the inner ear or specifically in outer hair cells of the inner ear were deaf. Experimental mechanical deflection of the ciliary bundle toward the tallest cilium failed to evoke currents from isolated outer hair cells from Tmie -null mice. However, deflection in the opposite direction elicited a current. Thus, assuming that there is only one mechanotransduction channel in these cells, this finding suggests that TMIE is not the pore-forming subunit. Expression of wild-type TMIE, but not TMIE with mutations associated with human deafness, rescued currents evoked by mechnical deflection toward the tallest cilium in outer hair cells from Tmie -null mice. Moreover, expression of a dominant-negative TMIE, which disrupted the interaction between TMIE, PCDH15, and LHFP15 in HEK293T cells, impaired mechanically-evoked activation of a genetically-encoded calcium sensor; whereas, mechanically-evoked calcium signaling was unaffected by expression of the dominant-negative TMIE construct bearing mutations associated with human deafness. Thus, this provides insight into how the deafness-associated protein TMIE participates in mechanical signal transduction in the ear. B. Zhao, Z. Wu, N. Grillet, L. Yan, W. Xiong, S. Harkins-Perry, U. Muller, TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84 , 954–967 (2014). [PubMed] W. Liedtke, A precisely defined role for the tip link-associated protein TMIE in the mechanoelectrical transduction channel complex of inner ear hair cells. Neuron 84 , 889–891 (2014). [PubMed]" @default.
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• W2064595024 date "2014-12-09" @default.
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• W2064595024 title "About TMIE to Hear" @default.
• W2064595024 doi "https://doi.org/10.1126/scisignal.aaa4348" @default.
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