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First published online 5 August 2008
doi: 10.1242/jcs.023705

Journal of Cell Science 121, 2871-2879 (2008)
Published by The Company of Biologists 2008
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Research Article

TRPV4 enhances the cellular uptake of aminoglycoside antibiotics

Takatoshi Karasawa1, Qi Wang1, Yi Fu2,3, David M. Cohen2,3 and Peter S. Steyger1,*

1 Oregon Hearing Research Center, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA
2 Division of Nephrology and Hypertension, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA
3 Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA

* Author for correspondence (e-mail: steygerp{at}ohsu.edu)

Accepted 28 May 2008

The cochlea and kidney are susceptible to aminoglycoside-induced toxicity. The non-selective cation channel TRPV4 is expressed in kidney distal tubule cells, and hair cells and the stria vascularis in the inner ear. To determine whether TRPV4 is involved in aminoglycoside trafficking, we generated a murine proximal-tubule cell line (KPT2) and a distal-tubule cell line (KDT3). TRPV4 expression was confirmed in KDT3 cells but not in KPT2 cells. Removal of extracellular Ca2+ significantly enhanced gentamicin–Texas-Red (GTTR) uptake by KDT3, indicative of permeation through non-selective cation channels. To determine whether TRPV4 is permeable to GTTR, stable cell lines were generated that express TRPV4 in KPT2 (KPT2-TRPV4). KPT2-TRPV4 cells took up more GTTR than control cell lines (KPT2-pBabe) in the absence of extracellular Ca2+. TRPV4-dependent GTTR uptake was abolished by a point mutation within the crucial pore region of the channel, suggesting that GTTR permeates the TRPV4 channel. In an endolymph-like extracellular environment, clearance of GTTR was attenuated from KPT2-TRPV4 cells in a TRPV4-dependent fashion. We propose that TRPV4 has a role in aminoglycoside uptake and retention in the cochlea.

Key words: Gentamicin, Ototoxicity, Aminoglycosides, Cochlea, Hair cells, Stria vascularis, TRPV4, Drug permeability






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