A Point Mutation in a Plasma Membrane Ca2+-ATPase Gene Causes Deafness in Wriggle Mouse Sagami

Takahashi, Katsumasa; Kitamura, Ken

doi:10.1006/bbrc.1999.1102

Cited by 104 publications

(80 citation statements)

References 22 publications

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“…In this study, decreased immunostaining for PMCA of the stereocilia and the cuticular plate of OHCs in gentamicin-treated ears was striking. The restricted presence of PMCA in the stereocilia and cuticular plate of OHCs (Crouch and Schulte 1995;Apicella et al 1997;Furuta et al 1998;Takahashi and Kitamura 1999;Street et al 1998) suggests that it may affect mechanoelectrical transduction through calcium ion regulation (see, e.g., Fettiplace et al 2001). It seems reasonable to assume that surviving hair cells with greatly reduced PMCA levels were not functioning normally.…”

Section: Cytochemical Effects Of Gentamicin Treatmentmentioning

confidence: 99%

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

Imamura

Adams

2003

JARO - Journal of the Association for Research in Otolaryngolog

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Effects of a single local dose of gentamicin upon sensory and nonsensory cells throughout the cochlea were assessed by changes in immunostaining patterns for a broad array of functionally important proteins. Cytochemical changes in hair cells, spiral ganglion cells, and cells of the stria vascularis, spiral ligament, and spiral limbus were found beginning 4 days post administration. The extent of changes in immunostaining varied with survival time and with cell type and was not always commensurate with the degree to which individual cell types accumulated gentamicin. Outer hair cells, types I and II fibrocytes of the spiral ligament, and fibrocytes in the spiral limbus showed marked decreases in immunostaining for a number of constituents. In contrast, inner hair cells, type III fibrocytes and root cells of the spiral ligament, cells of the stria vascularis, and interdental cells in the spiral limbus showed less dramatic decreases, and in some cases they showed increases in immunostaining. Results indicate that, in addition to damaging sensory cells, local application of gentamicin results in widespread and disparate disruptions of a variety of cochlear cell types. Only in the case of ganglion cells was it apparent that the changes in nonsensory cells were secondary to loss or damage of hair cells. These results indicate that malfunction of the ear following gentamicin treatment is widespread and far more complex than simple loss of sensory elements. The results have implications for efforts directed toward detecting, preventing, and treating toxic effects of aminoglycosides upon the inner ear.

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Section: Cytochemical Effects Of Gentamicin Treatmentmentioning

confidence: 99%

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

Imamura

Adams

2003

JARO - Journal of the Association for Research in Otolaryngolog

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“…Although all four PMCA gene products and many splice variants are expressed in the mammalian cochlea (Crouch and Schulte, 1996;Furuta et al, 1998), only PMCA2 is known to be essential for hearing and balance (Noben-Trauth et al, 1997;Kozel et al, 1998;Street et al, 1998;Takahashi and Kitamura, 1999). PMCA2 with the 2a variant at splice-site C is the only PMCA expressed in frog and rat hair bundles (Dumont et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Hill

Williams

LeMasurier

et al. 2006

Journal of Neuroscience

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Localization of mechanotransduction in sensory hair cells to hair bundles requires selective targeting of essential proteins to specific locations. Isoform 2 of the plasma-membrane Ca 2ϩ -ATPase (PMCA2), required for hearing and balance, is found exclusively in hair bundles. We determined the contribution of splicing at the two major splicing sites (A and C) to hair-cell targeting of PMCA2. When PMCA2 isoforms were immunoprecipitated from purified hair bundles of rat utricle, 2w was the only site A variant detected; moreover, immunocytochemistry for 2w in rat vestibular and cochlear tissues indicated that this splice form was located solely in bundles. To demonstrate the necessity of the 2w sequence, we transfected hair cells with PMCA2 containing different variants at splice sites A and C. Although native hair bundles exclusively use the 2a form at splice-site C, epitope-tagged PMCA2w/a and PMCA2w/b were both concentrated in bundles, indicating that site C is not involved in bundle targeting. In contrast, PMCA2z/a was excluded from bundles and was instead targeted to the basolateral plasma membrane. Bundle-specific targeting of PMCA2w/a tagged with green fluorescent protein (GFP) was diminished, suggesting that GFP interfered with splice-site A. Together, these data demonstrate that PMCA2w/a is the hairbundle isoform of PMCA in rat hair cells and that 2w targets PMCA2 to bundles. The 2w sequence is thus the first targeting signal identified for a hair-bundle membrane protein; moreover, the striking distribution of inner-ear PMCA isoforms dictated by selective targeting suggests a critical functional role for segregated pathways of Ca 2ϩ transport.

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“…This strategy has been successfully used to generate PMCA2-deficient mice that suffer from deafness and balance deficits (22), supported by analyses of "deafwaddler" and "wriggle mouse Sagami" mouse strains, both showing a phenotype comparable with the PMCA2-deficient mice and also harboring spontaneous mutations in the PMCA2 gene (23,24).…”

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confidence: 99%

Plasma Membrane Ca2+ ATPase 4 Is Required for Sperm Motility and Male Fertility

Schuh

Cartwright

Jankevics

et al. 2004

Journal of Biological Chemistry

235

202

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Calcium and Ca 2؉ -dependent signals play a crucial role in sperm motility and mammalian fertilization, but the molecules and mechanisms underlying these Ca 2؉ -dependent pathways are incompletely understood. Here we show that homozygous male mice with a targeted gene deletion of isoform 4 of the plasma membrane calcium/ calmodulin-dependent calcium ATPase (PMCA), which is highly enriched in the sperm tail, are infertile due to severely impaired sperm motility. Furthermore, the PMCA inhibitor 5-(and-6)-carboxyeosin diacetate succinimidyl ester reduced sperm motility in wild-type animals, thus mimicking the effects of PMCA4 deficiency on sperm motility and supporting the hypothesis of a pivotal role of the PMCA4 on the regulation of sperm function and intracellular Ca 2؉ levels.Successful fertilization requires the sperm to travel long distances and undergo capacitation prior to reaching the female egg. After reaching their target, the sperm must interact with the extracellular matrix of the egg, including proteins of the zona pellucida, and release acrosomal material. Calcium is considered to exert a function on most, if not all, of these processes. In this field, most of the work on Ca 2ϩ signaling has focused on Ca 2ϩ entry mechanisms, especially on the role of Ca 2ϩ channels (1-4). For example, gene ablation of the cation channel of sperm (CatSper) leads to impaired sperm motility and male infertility (5), and mice lacking the mitochondrial voltage-dependent anion channel type 3 (VDAC3) are also infertile due to immotile sperm (6). These results show that tight regulation of ion entry by ion channels is critical to sperm function. Although there is little doubt as to the importance of calcium homeostasis in sperm motility and fertilization (7-12), the function of the plasma membrane Ca 2ϩ /calmodulin-dependent Ca 2ϩ ATPase (PMCA) 1 during this process remained enigmatic.PMCA represents a family of enzymes that extrude calcium from the cytosol across the plasma membrane of eukaryotic cells. Since their initial identification in erythrocytes (13), four different isoforms have been identified, and multiple splice forms of these isoforms have been described. The well defined tissue-specific expression pattern of different isoforms and splice variants of the pump in various mammalian tissues (14) and the regulated expression pattern during mouse development (15) strongly suggest a specific physiological function for each isoform and splice variant (reviewed in Strehler and Zacharias (16)). The identification of physical and functional interaction partners of the Ca 2ϩ pump has given insights into the putative functions of PMCAs as regulators of Ca 2ϩ -dependent signal transduction processes (17-21). Interaction of PMCA2 and -4 "b" splice variants was shown to be mediated by the PDZ-(PSD-95/Dlg/ZO-1) domain of the corresponding interaction partner and the C termini of the PMCA isoform (which harbors a typical PDZ domain binding motif (17)). Both modes of interaction with PDZ domain-containing proteins, specific and...

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A Point Mutation in a Plasma Membrane Ca2+-ATPase Gene Causes Deafness in Wriggle Mouse Sagami

Cited by 104 publications

References 22 publications

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Plasma Membrane Ca2+ ATPase 4 Is Required for Sperm Motility and Male Fertility

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