TRPML3 mutations cause impaired mechano‐electrical transduction and depolarization by an inward‐rectifier cation current in auditory hair cells of varitint‐waddler mice

Aken, Alexander F. J. van; Atiba-Davies, Margaret; Marcotti, Walter; Goodyear, Richard J.; Bryant, Jane E.; Richardson, Guy P.; Noben-Trauth, Konrad; Kros, Corné J.

doi:10.1113/jphysiol.2008.156992

Cited by 60 publications

(57 citation statements)

References 44 publications

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“…Endogenous MCOLN3 localizes mainly to intracellular vesicles in hair cells, whereas lower levels of the protein are also observed at the plasma membrane of the stereocilia (1,7). In HeLa and human fibroblasts, endogenous MCOLN3 was found to be distributed along the endocytic pathway (8,9).…”

Section: Mucolipin-3 (Mcoln3)mentioning

confidence: 95%

Mucolipin-3 Regulates Luminal Calcium, Acidification, and Membrane Fusion in the Endosomal Pathway

Lelouvier

Puertollano

2011

Journal of Biological Chemistry

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Section: Mucolipin-3 (Mcoln3)mentioning

confidence: 95%

Mucolipin-3 Regulates Luminal Calcium, Acidification, and Membrane Fusion in the Endosomal Pathway

Lelouvier

Puertollano

2011

Journal of Biological Chemistry

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“…Although TRPML3 is expressed in the inner ear (Nagata et al 2008;Van Aken et al 2008;Grimm et al 2009;Takumida and Anniko 2009), our expression screen did not reveal large changes in expression between E17 and P8. TRPML3 showed a shallow RNA expression gradient during development and across the organ.…”

Section: Trp Subunits With No or Little Expression And/or No Distinctmentioning

confidence: 66%

“…The transduction channel is a nonselective cation channel with a conductance of about 100 pS, permeable to calcium and sensitive to inhibition by TRP channel antagonists, ruthenium red, and lanthanum in turtle (Farris et al 2004) and mouse (Géléoc and Holt, unpublished). Several TRP channel subunits have been presented as hair cell transduction channel candidates, including TRPN1 (Walker et al 2000), TRPV4 (Liedtke et al 2000), TRPA1 (Corey et al 2004), and recently, TRPML3 ; Nagata et van Aken et al 2008). Yet, targeted gene deletion of single TRP genes has not revealed deficits in hair cell mechanotransduction.…”

Section: Introductionmentioning

confidence: 99%

“…TRPV4 is expressed in hair cells, stria vascularis, and vestibular dark cells (Liedtke et al 2000;Takumida et al 2005), and disruption of TRPV4 causes delayed-onset hearing loss and increases susceptibility to acoustic injury (Tabuchi et al 2005). TRPML3 is expressed in sensory hair cells and in the marginal cells of the stria vascularis (Di Palma et al 2002;Nagata et al 2008;Van Aken et al 2008). Mutations in TRPML3 lead to deafness in varitintwaddler (Va) mice due to defects in stria vascularis and hair cells.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in TRPML3 lead to deafness in varitintwaddler (Va) mice due to defects in stria vascularis and hair cells. The Va mutation induces constitutive activation of inward currents which causes cellular degeneration (Nagata et al 2008;Van Aken et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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A Quantitative Analysis of the Spatiotemporal Pattern of Transient Receptor Potential Gene Expression in the Developing Mouse Cochlea

Asai

Holt

Géléoc

2009

JARO

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TRP genes encode a diverse family of ion channels which have been implicated in many sensory functions. Because several TRP channels have similar properties to the elusive hair cell transduction channel, recent attention has focused on TRP gene expression in the inner ear. At least four TRP genes are known to be expressed in hair cells: TRPC3, TRPV4, TRPA1, and TRPML3. However, there is little evidence supporting any of these as a component of the transduction complex. Other less well-characterized TRP channels are expressed in the inner ear, in particular, within the organ of Corti. Because of their potential role in sensory function, we investigated the developmental expression of RNA that encodes all 33 TRP subunits as well as several splice variants. We designed a quantitative PCR screen using cochlear samples acquired before, during, and after the time when mechanotransduction is acquired in sensory hair cells (embryonic day 17 to postnatal day 8). Cochleas, which included the organ of Corti, stria vascularis, and Reissner's membrane, were subdivided into four equal quadrants which allowed for regional comparison during development. Expression of RNA transcripts that encoded 33 TRP subunits plus several splice forms and beta-actin were quantified in 28 samples for a total of 1,092 individual measurements, each done in triplicate. We detected RNA that encoded all TRP channels except two: TRPC7 and TRPM8. The largest changes in RNA expression were for TRPA1 (9100-fold), which suggested that these subunits may contribute to normal cochlear function. Furthermore, the screen revealed TRPP3 and PKD1L3 RNA expression patterns that were correlated with the acquisition of sensory transduction in outer hair cells (Lelli et al., J Neurophysiol. 101:2961-2973, 2009). Numerous spatiotemporal expression gradients were identified many of which may contribute to the normal functional development of the mouse cochlea.

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Expression and vesicular localization of mouse Trpml3 in stria vascularis, hair cells, and vomeronasal and olfactory receptor neurons

et al. 2011

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TRPML3 is a member of the mucolipin branch of the transient receptor potential cation channel family. A dominant missense mutation in Trpml3 (also known as Mcoln3) causes deafness and vestibular impairment characterized by stereocilia disorganization, hair cell loss, and endocochlear potential reduction. Both marginal cells of the stria vascularis and hair cells express Trpml3 mRNA. Here we used in situ hybridization, quantitative RT-qPCR, and immunohistochemistry with several antisera raised against TRPML3 to determine the expression and subcellular distribution of TRPML3 in the inner ear as well as in other sensory organs. We also use Trpml3 knockout tissues to distinguish TRPML3-specific from nonspecific immunoreactivities. We find that TRPML3 localizes to vesicles of hair cells and strial marginal cells but not to stereociliary ankle links or pillar cells, which nonspecifically react with two antisera raised against TRPML3. Upon cochlear maturation, TRPML3 protein is redistributed to perinuclear vesicles of strial marginal cells and is augmented in inner hair cells vs. outer hair cells. Mouse somato-sensory neurons, retinal neurons, and taste receptor cells do not appear to express physiologically relevant levels of TRPML3. Finally, we found that vomeronasal and olfactory sensory receptor cells do express TRPML3 mRNA and protein, which localizes to vesicles in their somas and dendrites as well as at apical den dritic knobs.

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TRPML3 mutations cause impaired mechano‐electrical transduction and depolarization by an inward‐rectifier cation current in auditory hair cells of varitint‐waddler mice

Abstract: TRPML3 (mucolipin-3

Cited by 60 publications

References 44 publications

Mucolipin-3 Regulates Luminal Calcium, Acidification, and Membrane Fusion in the Endosomal Pathway

Mucolipin-3 Regulates Luminal Calcium, Acidification, and Membrane Fusion in the Endosomal Pathway

A Quantitative Analysis of the Spatiotemporal Pattern of Transient Receptor Potential Gene Expression in the Developing Mouse Cochlea

Expression and vesicular localization of mouse Trpml3 in stria vascularis, hair cells, and vomeronasal and olfactory receptor neurons

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