Exp Mol Med.  2013 Mar;45(3):e12.

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

• Lee JH
• Park C
• Kim SJ
• Kim HJ
• Oh GS
• Shen A
• So HS
• Park R

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.

Keyword

gentamicin; hair cells; ototoxicity; TRPV1; TRPV4

MeSH Terms

Animals
Cell Death/drug effects
Cell Polarity/drug effects
Cell Survival/drug effects
Dose-Response Relationship, Drug
Gadolinium/metabolism
Gentamicins/*metabolism/pharmacology
Hair Cells, Auditory/drug effects/*metabolism
Hair Cells, Auditory, Inner/drug effects/metabolism
Rats
Rats, Sprague-Dawley
Ruthenium Red/metabolism
TRPV Cation Channels/*metabolism
Time Factors
Xanthenes/metabolism
Zebrafish
Gentamicins
TRPV Cation Channels
Xanthenes
Ruthenium Red
Gadolinium