title: Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability.
abstract: 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.
authors.affiliation: Vestibulocochlear Research Center, Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, South Korea.
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Channy
authors.initials: C
authors.lastname: Park
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Gi-Su
authors.initials: GS
authors.lastname: Oh
authors.forename: AiHua
authors.initials: A
authors.lastname: Shen
authors.forename: Hong-Seob
authors.initials: HS
authors.lastname: So
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000378:metabolism; D005839:Gentamicins / Q000378:metabolism* / Q000494:pharmacology; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism*; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D013997:Time Factors; D014966:Xanthenes / Q000378:metabolism; D015027:Zebrafish
chemical_list: D005839:Gentamicins; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C486577:Trpv4 protein, rat; D014966:Xanthenes; D012430:Ruthenium Red; C034657:Texas red; D005682:Gadolinium