Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability

Hair cells at the base of the cochlea appear to be more susceptible to damage by the aminoglycoside gentamicin than those at the apex. However, the mechanism of base-to-apex gradient ototoxicity by gentamicin remains to be elucidated. We report here that gentamicin caused rodent cochlear hair cell damages in a time- and dose-dependent manner. Hair cells at the basal turn were more vulnerable to gentamicin than those at the apical turn. Gentamicin-conjugated Texas Red (GTTR) uptake was predominant in basal turn hair cells in neonatal rats. Transient receptor potential vanilloid 1 (TRPV1) and 4 (TRPV4) expression was confirmed in the cuticular plate, stereocilia and hair cell body of inner hair cells and outer hair cells. The involvement of TRPV1 and TRPV4 in gentamicin trafficking of hair cells was confirmed by exogenous calcium treatment and TRPV inhibitors, including gadolinium and ruthenium red, which resulted in markedly inhibited GTTR uptake and gentamicin-induced hair cell damage in rodent and zebrafish ototoxic model systems. These results indicate that the cytotoxic vulnerability of cochlear hair cells in the basal turn to gentamicin may depend on effective uptake of the drug, which was, in part, mediated by the TRPV1 and TRPV4 proteins. Antibiotics: Why gentamicin kills only some inner-ear hair cells A pair of channel proteins, TRPV1 and TRPV4, expressed by the hair cells deep inside the cochlea of the inner-ear are responsible for transporting the antibiotic gentamicin. This helps explain why the ear-damaging drug causes more harm at the base of the cochlea than at the apex of the inner ear structure, where the proteins are less abundant. A team led by Hong-Seob So and Raekil Park at the Wonkwang University School of Medicine, Korea, tracked gentamicin uptake using a fluorescent-tagged version of the drug injected into the inner ears of newborn rats. Working again in rodents as well as a zebrafish model of hearing loss, the authors then added drugs to block TRPV1 and TRPV4, which are expressed preferentially in the middle and basal turns of the cochlea. This resulted in reduced gentamicin-induced hair cell damage.