Function coupling of otoferlin with GAD65 acts to modulate GABAergic activity

Wu, Wu; Rahman, Mona N.; Guo, Jun; Roy, Natalie; Xue, Ling; Cahill, Catherine M.; Zhang, Shetuan; Jia, Zongchao

doi:10.1093/jmcb/mjv011

Cited by 9 publications

(11 citation statements)

References 45 publications

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“…A recent study concluded that otoferlin both directly interacts with glutamate decarboxylase (GAD) and affected GAD transcript levels (Sarro et al 2008;Noh et al 2010;Wu et al 2015). We therefore measured GAD and GABA receptor subunit expression levels in WT and mutant larvae (Figure 8).…”

Section: Otofb Mutants Display Abnormal Transcript Levels Of Gabar Subunits and Gadmentioning

confidence: 99%

Truncation of the otoferlin transmembrane domain alters the development of hair cells and reduces membrane docking

Manchanda

Bonventre

Bugel

et al. 2021

MBoC

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Release of neurotransmitter from sensory hair cells is regulated by otoferlin. Despite the importance of otoferlin in the auditory and vestibular pathways, the functional contributions of the domains of the protein have not been fully characterized. Using a zebrafish model, we investigated a mutant otoferlin with a stop codon at the start of the transmembrane domain. We found that both the phenotype severity and the expression level of mutant otoferlin changed with the age of the zebrafish. At the early developmental timepoint of 72 hours post-fertilization (hpf) low expression of the otoferlin mutant coincided with synaptic ribbon deficiencies, reduced endocytosis, and abnormal transcription of several hair cell genes. As development proceeded, expression of the mutant otoferlin increased, and both synaptic ribbons and hair cell transcript levels resembled wild type. However, hair cell endocytosis deficits and abnormalities in the expression of GABA receptors persisted even after upregulation of mutant otoferlin. Analysis of membrane-reconstituted otoferlin measurements suggest a function for the transmembrane domain in liposome docking. We conclude that that deletion of the transmembrane domain reduces membrane docking, attenuates endocytosis, and results in developmental delay of the hair cell.

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Section: Otofb Mutants Display Abnormal Transcript Levels Of Gabar Subunits and Gadmentioning

confidence: 99%

Truncation of the otoferlin transmembrane domain alters the development of hair cells and reduces membrane docking

Manchanda

Bonventre

Bugel

et al. 2021

MBoC

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“…Inactivation of either of these genes results in profound deafness (Platzer et al 2000;Roux et al 2006). Otoferlin has been detected in several brain regions, including hippocampal neurons expressing GAD65, a marker of inhibitory neurons (Roux et al 2006;Wu et al 2015), but no functional deficit has yet been characterized in the brains of any of the GABA/glycinergic to purely glycinergic transmission of MNTB neurons (Hirtz et al 2011(Hirtz et al , 2012Satheesh et al 2012).…”

Section: A) the Auditory Ribbon Synapsementioning

confidence: 99%

Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems

Michalski

Petit

2019

Annu. Rev. Neurosci.

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The genetic approach, based on the study of inherited forms of deafness, has proven to be particularly effective for deciphering the molecular mechanisms underlying the development of the peripheral auditory system, the cochlea and its afferent auditory neurons, and how this system extracts the physical parameters of sound. Although this genetic dissection has provided little information about the central auditory system, scattered data suggest that some genes may have a critical role in both the peripheral and central auditory systems. Here, we review the genes controlling the development and function of the peripheral and central auditory systems, focusing on those with demonstrated intrinsic roles in both systems and highlighting the current underappreciation of these genes. Their encoded products are diverse, from transcription factors to ion channels, as are their roles in the central auditory system, mostly evaluated in brainstem nuclei. We examine the ontogenetic and evolutionary mechanisms that may underlie their expression at different sites.

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“…Firstly, these cell cultures are mostly composed of cells with cholinergic characteristics (Kovalevich & Langford, 2013). However, both GABAergic and glutamatergic systems have been previously explored in these cultures (Kim et al, 2008;Lu et al, 2009;Mendell et al, 2018;Wu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

Gladulich

Xie

Jensen

et al. 2020

Journal of Neurochemistry

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The regulation of protein synthesis is a vital and finely tuned process in cellular physiology. In neurons, this process is very precisely regulated, as which mRNAs undergo translation is highly dependent on context. One of the most prominent regulators of protein synthesis is the enzyme eukaryotic elongation factor kinase 2 (eEF2K) that regulates the elongation stage of protein synthesis. This kinase and its substrate, eukaryotic elongation factor 2 (eEF2) are important in processes such as neuronal development and synaptic plasticity. eEF2K is regulated by multiple mechanisms including Ca 2+ -ions and the mTORC1 signaling pathway, both of which play key roles in neurological processes such as learning and memory. In such settings, the localized control of protein synthesis is of crucial importance. In this work, we sought to investigate how the localization of eEF2K is controlled and the impact of this on protein synthesis in neuronal cells. In this study, we used both SH-SY5Y neuroblastoma cells and mouse cortical neurons, and pharmacologically and/or genetic approaches to modify eEF2K function. We show that eEF2K activity and localization can be regulated by its binding partner Homer1b/c, a scaffolding protein known for its participation in calcium-regulated signaling pathways. Furthermore, our results indicate that this interaction is regulated by the mTORC1 pathway, through a known phosphorylation site in eEF2K (S396), and that it affects rates of localized protein synthesis at synapses depending on the presence or absence of this scaffolding protein.

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Function coupling of otoferlin with GAD65 acts to modulate GABAergic activity

Cited by 9 publications

References 45 publications

Truncation of the otoferlin transmembrane domain alters the development of hair cells and reduces membrane docking

Truncation of the otoferlin transmembrane domain alters the development of hair cells and reduces membrane docking

Genes Involved in the Development and Physiology of Both the Peripheral and Central Auditory Systems

Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1‐dependent phosphorylation

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