The Cation Channel TMEM63B Is an Osmosensor Required for Hearing

Du, Han; Ye, Chang; Wu, Dan; Zang, Yang; Zhang, Linqing; Chen, Chen; He, Xueyan; Yang, Jing; Hu, Ping; Xu, Zhengfeng; Wan, Guoqiang; Shi, Yun

doi:10.1016/j.celrep.2020.107596

Cited by 54 publications

(108 citation statements)

References 75 publications

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“…The Q/R editing affects Ca 2+ permeability of Tmem63b channel Tmem63 family are osmosensitive (or mechanosensitive) cation channels (27,39). Their plant orthologue OSCA channels are also osmosensitive and mechanosensitive (39)(40)(41).…”

Section: Presence Of Exon 4 Suppresses Q/r Editing In Tmem63bmentioning

confidence: 99%

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Distant coupling between RNA editing and alternative splicing of the osmosensitive cation channel Tmem63b

Zang

Shi

et al. 2020

Journal of Biological Chemistry

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Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ~80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5’ end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in brain.

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Section: Presence Of Exon 4 Suppresses Q/r Editing In Tmem63bmentioning

confidence: 99%

“…We recently demonstrated that Tmem63s are osmosensitive cation channels activated by hypotonic stress and mediate extracellular Ca 2+ influx (27). We have established that the most sensitive measurement for the osmosensitivity was the percentage of cells responding to hypotonic stress (27).…”

Section: The Splicing and Editing Regulate Hypoosmolarity-induced Ca mentioning

confidence: 99%

Distant coupling between RNA editing and alternative splicing of the osmosensitive cation channel Tmem63b

Zang

Shi

et al. 2020

Journal of Biological Chemistry

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“…New ion channels are continuously being uncovered. For instance, it was recently shown that the stretch-activated nonselective cation channel TMEM63B is an osmosensor that can mediate the Ca 2+ influx [101]. This example indicates that it cannot be excluded that genes coding for Ca 2+ -transport proteins and contributing to Ca 2+ signaling were missed in the present work.…”

Section: Discussionmentioning

confidence: 77%

Transcriptomic Profiling of Ca2+ Transport Systems during the Formation of the Cerebral Cortex in Mice

Bouron

2020

Cells

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Cytosolic calcium (Ca2+) transients control key neural processes, including neurogenesis, migration, the polarization and growth of neurons, and the establishment and maintenance of synaptic connections. They are thus involved in the development and formation of the neural system. In this study, a publicly available whole transcriptome sequencing (RNA-Seq) dataset was used to examine the expression of genes coding for putative plasma membrane and organellar Ca2+-transporting proteins (channels, pumps, exchangers, and transporters) during the formation of the cerebral cortex in mice. Four ages were considered: embryonic days 11 (E11), 13 (E13), and 17 (E17), and post-natal day 1 (PN1). This transcriptomic profiling was also combined with live-cell Ca2+ imaging recordings to assess the presence of functional Ca2+ transport systems in E13 neurons. The most important Ca2+ routes of the cortical wall at the onset of corticogenesis (E11–E13) were TACAN, GluK5, nAChR β2, Cav3.1, Orai3, transient receptor potential cation channel subfamily M member 7 (TRPM7) non-mitochondrial Na+/Ca2+ exchanger 2 (NCX2), and the connexins CX43/CX45/CX37. Hence, transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1), transmembrane protein 165 (TMEM165), and Ca2+ “leak” channels are prominent intracellular Ca2+ pathways. The Ca2+ pumps sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and plasma membrane Ca2+ ATPase 1 (PMCA1) control the resting basal Ca2+ levels. At the end of neurogenesis (E17 and onward), a more numerous and diverse population of Ca2+ uptake systems was observed. In addition to the actors listed above, prominent Ca2+-conducting systems of the cortical wall emerged, including acid-sensing ion channel 1 (ASIC1), Orai2, P2X2, and GluN1. Altogether, this study provides a detailed view of the pattern of expression of the main actors participating in the import, export, and release of Ca2+. This work can serve as a framework for further functional and mechanistic studies on Ca2+ signaling during cerebral cortex formation.

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“…region replaced by eGFP after the start codon [20]. At P3, both homozygous Pou4f3(Δ/Δ) and Pou4f3(-/-) showed extensive degeneration of hair cells, while hair cells of both heterozygous mice were normal ( Fig 3A and 3B).…”

Section: Plos Geneticsmentioning

confidence: 98%

“…Pou4f3 knockout mice were generated by replacing the coding sequence after start codon by EGFP [20]. Mice used in this study were either maintained on C57BL/6J background or a mixed background of C57BL/6J and FVBN.…”

Section: Animalsmentioning

confidence: 99%

Aldh inhibitor restores auditory function in a mouse model of human deafness

Zhu

Gong

et al. 2020

PLoS Genet

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Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.

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The Cation Channel TMEM63B Is an Osmosensor Required for Hearing

Abstract: Highlights d TMEM63B is a hypo-osmolarity-activated cation channel d Deficiency of TMEM63B causes hearing loss in mice d TMEM63B is localized in hair cells and required for outer hair cell survival d TMEM63B mediates Ca 2+ -dependent regulatory volume decrease in outer hair cells

Cited by 54 publications

References 75 publications

Distant coupling between RNA editing and alternative splicing of the osmosensitive cation channel Tmem63b

Distant coupling between RNA editing and alternative splicing of the osmosensitive cation channel Tmem63b

Transcriptomic Profiling of Ca2+ Transport Systems during the Formation of the Cerebral Cortex in Mice

Aldh inhibitor restores auditory function in a mouse model of human deafness

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