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

Lee, Jeong-Han; Park, Channy; Kim, Se-Jin; Kim, Hyungjin; Oh, Gi‐Su; Shen, AiHua; So, Hong-Seob; Park, Raekil

doi:10.1038/emm.2013.25

Cited by 56 publications

(50 citation statements)

References 56 publications

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“…Similarly, several of the nonselective TRPV3 inhibitors listed in Table 2 were also identified as ototoxins (Coffin et al 2010). Although not investigated, the results presented herein could indicate a critical role for TRPV3 in hair cell physiology and ototoxicity, as has been suggested for TRPA1, V1, and V4 (Mukherjea et al 2008;Stepanyan et al 2011;Lee et al 2013).…”

Section: Discussionsupporting

confidence: 55%

Drofenine: a 2‐APB analog with improved selectivity for human TRPV3

Deering-Rice

Mitchell

Romero

et al. 2014

Pharmacology Res & Perspec

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Transient receptor potential vanilloid-3 (TRPV3) is a member of the TRPV subfamily of TRP ion channels. The physiological functions of TRPV3 are not fully understood, in part due to a lack of selective agonists and antagonists that could both facilitate the elucidation of roles for TRPV3 in mammalian physiology, as well as potentially serve as therapeutic agents to modulate conditions for which altered TRPV3 function has been implicated. In this study, the Microsource Spectrum Collection was screened for TRPV3 agonists and antagonists using alterations in calcium flux in TRPV3 over-expressing HEK-293 cells. The antispasmodic agent drofenine was identified as a new TRPV3 agonist. Drofenine exhibited similar potency to the known TRPV3 agonists 2-aminoethoxydiphenylboronate (2-APB) and carvacrol in HEK-293 cells, but greater selectivity for TRPV3 based on a lack of activation of TRPA1, V1, V2, V4, or M8. Multiple inhibitors were also identified, but all of the compounds were either inactive or not specific. Drofenine activated TRPV3 via interactions with the residue, H426, which is required for TRPV3 activation by 2-APB. Drofenine was a more potent agonist of TRPV3 and more cytotoxic than either carvacrol or 2-APB in human keratinocytes and its effect on TRPV3 in HaCaT cells was further demonstrated using the antagonist icilin. Due to the lack of specificity of existing TRPV3 modulators and the expression of multiple TRP channels in cells/tissue, drofenine may be a valuable probe for elucidating TRPV3 functions in complex biological systems. Identification of TRPV3 as a target for drofenine may also suggest a mechanism by which drofenine acts as a therapeutic agent.

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Section: Discussionsupporting

confidence: 55%

Drofenine: a 2‐APB analog with improved selectivity for human TRPV3

Deering-Rice

Mitchell

Romero

et al. 2014

Pharmacology Res & Perspec

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“…Intrinsic cellular fluorescence was measured using a 60×, 0.9 NA water immersion lens (Olympus). [49][50][51][52] Intensity and lifetime images were acquired by using four successive scans of a single-focal plane with an average laser power of 5 mW at the sample and a total image acquisition time of 124 s. To prevent photobleaching, no more than three images were obtained from well-separated cochlear regions. Intrinsic fluorescence was isolated using a 500-nm longpass dichroic mirror and an HQ 460∕80 bandpass filter (Chroma Technology, Bellows Falls, Vermont), and detected with a Hamamatsu H7422p-40 photon-counting PMT (Hammamatsu, Hammamatsu City, Japan) and a time-correlated single-photon counting module (830 SPC, Becker and Hickl, Berlin, Germany).…”

Section: Metabolic Imaging Methodsmentioning

confidence: 99%

Gentamicin differentially alters cellular metabolism of cochlear hair cells as revealed by NAD(P)H fluorescence lifetime imaging

et al. 2015

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Aminoglycoside antibiotics are implicated as culprits of hearing loss in more than 120,000 individuals annually. Research has shown that the sensory cells, but not supporting cells, of the cochlea are readily damaged and/or lost after use of such antibiotics. High-frequency outer hair cells (OHCs) show a greater sensitivity to antibiotics than high- and low-frequency inner hair cells (IHCs). We hypothesize that variations in mitochondrial metabolism account for differences in susceptibility. Fluorescence lifetime microscopy was used to quantify changes in NAD(P)H in sensory and supporting cells from explanted murine cochleae exposed to mitochondrial uncouplers, inhibitors, and an ototoxic antibiotic, gentamicin (GM). Changes in metabolic state resulted in a redistribution of NAD(P)H between subcellular fluorescence lifetime pools. Supporting cells had a significantly longer lifetime than sensory cells. Pretreatment with GM increased NAD(P)H intensity in high-frequency sensory cells, as well as the NAD(P)H lifetime within IHCs. GM specifically increased NAD(P)H concentration in high-frequency OHCs, but not in IHCs or pillar cells. Variations in NAD(P)H intensity in response to mitochondrial toxins and GM were greatest in high-frequency OHCs. These results demonstrate that GM rapidly alters mitochondrial metabolism, differentially modulates cell metabolism, and provides evidence that GM-induced changes in metabolism are significant and greatest in high-frequency OHCs.

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“…In addition to aging, hair cells are also susceptible to injury from trauma and aminoglycoside ototoxicity, while supporting cells are less vulnerable (Lee et al, 2013). Since these factors also contribute to BPPV, protecting or regenerating sensory hair cells are possible strategies to treat vestibular dysfunction (Cabrera Kang and Tusa, 2013).…”

Section: Degeneration and Regeneration Of Otoconiamentioning

confidence: 99%

Mechanisms of otoconia and otolith development

Lundberg

Thiessen

et al. 2014

Developmental Dynamics

131

134

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Otoconia are bio-crystals which couple mechanic forces to the sensory hair cells in the utricle and saccule, a process essential for us to sense linear acceleration and gravity for the purpose of maintaining bodily balance. In fish, structurally similar bio-crystals called otoliths mediate both balance and hearing. Otoconia abnormalities are common and can cause vertigo and imbalance in humans. However, the molecular etiology of these illnesses is unknown, as investigators have only begun to identify genes important for otoconia formation in recent years. To date, in-depth studies of selected mouse otoconial proteins have been performed, and about 75 zebrafish genes have been identified to be important for otolith development. This review will summarize recent findings as well as compare otoconia and otolith development. It will provide an updated brief review of otoconial proteins along with an overview of the cells and cellular processes involved. While continued efforts are needed to thoroughly understand the molecular mechanisms underlying otoconia and otolith development, it is clear that the process involves a series of temporally and spatially specific events that are tightly coordinated by numerous proteins. Such knowledge will serve as the foundation to uncover the molecular causes of human otoconia-related disorders.

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

Cited by 56 publications

References 56 publications

Drofenine: a 2‐APB analog with improved selectivity for human TRPV3

Drofenine: a 2‐APB analog with improved selectivity for human TRPV3

Gentamicin differentially alters cellular metabolism of cochlear hair cells as revealed by NAD(P)H fluorescence lifetime imaging

Mechanisms of otoconia and otolith development

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