Inhibition of K+ currents in type I vestibular hair cells by gentamicin and neomycin.
Significant ototoxicity limits the use of aminoglycoside (AG) antibiotics. Several mechanisms may contribute to the death of both auditory and vestibular hair cells. In this study the effects of gentamicin and neomycin on K(+) currents in mature and early postnatal type I vestibular hair cells (HCI) were tested directly. The whole-cell patch clamp technique was used to assess the effects of AG and KCNQ channel modulators on K(+) currents (IK) in HCI acutely isolated from gerbil semicircular canals. Extracellular neomycin (1 mM) rapidly reduced peak outward IK by 16 ± 4% (n = 9) in mature HCI (postnatal days, P, 25-66). Gentamicin (5 mM) reduced outward IK by 16 ± 3% (n = 8). A similar reduction in outward current was seen in immature HCI (P5-9) that lacked the low-voltage-activated component of IK observed in mature cells. Intracellular application of gentamicin and neomycin also reduced IK in mature HCI. Modulators of KCNQ channels were used to probe KCNQ channel involvement. The selective KCNQ antagonist XE991 did not reduce IK and the neomycin-induced reduction in IK was not reversed by the KCNQ agonist flupirtine. Application of intracellular poly-D-lysine to sequester PIP2 did not reduce IK. Application of the K(+) channel blocker 4-aminopyridine (4-AP) strongly reduced IK, and extracellular AG in the presence of 4-AP gave no further inhibition of IK. In summary, AG significantly reduce the 4-AP-sensitive IK in early postnatal and mature HCI. K(+) current inhibition differs from that seen in outer hair cells, since it does not appear to involve PIP2 sequestration or KCNQ channels.
Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colo., USA.
Scott E
SE
Mann
Matthew
M
Johnson
Frances L
FL
Meredith
Katherine J
KJ
Rennie
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005260:Female; D005839:Gentamicins / Q000494:pharmacology*; D005849:Gerbillinae; D018069:Hair Cells, Vestibular / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009355:Neomycin / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D009355:Neomycin