TRPA1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells.

摘要: Aminoglycoside ototoxicity involves the accumulation of antibiotic molecules in inner ear hair cells and subsequent degeneration these cells. The exact route entry aminoglycosides into vivo is still unknown. Similar to other small organic cations, could be brought cell by endocytosis or permeate through large non-selective cation channels, such as mechanotransduction channels ATP-gated P2X channels. Here, we show that aminoglycoside gentamicin can enter mouse outer (OHCs) via TRPA1, activated certain pungent compounds endogenous products lipid peroxidation. Using conventional perforated whole-cell patch clamp recordings, found application TRPA1 agonists initiates inward current responses wild-type OHCs, but not OHCs homozygous Trpa1 knockout mice. consistent with activation were observed heterologous transfected Trpa1. Upon brief agonists, Trpa1-transfected become loaded fluorescent gentamicin–Texas Red conjugate (GTTR). This uptake was mock-transfected non-transfected In organ Corti explants, resulted rapid GTTR another cationic dye, FM1-43, some supporting cells, even when disrupted pre-incubation calcium-free solution. TRPA1-mediated FM1-43 mice blocked PPADS, a blocker Notably, 4-hydroxynonenal, an molecule known generated during episodes oxidative stress accumulate cochlea after noise exposure. We concluded may provide novel pathway for OHCs.