Calcium Regulates Molecular Interactions of Otoferlin with Soluble NSF Attachment Protein Receptor (SNARE) Proteins Required for Hair Cell Exocytosis

Ramakrishnan, Neeliyath A.; Drescher, Marian J.; Morley, Barbara J.; Kelley, Philip M.; Drescher, Dennis G.

doi:10.1074/jbc.m113.480533

Cited by 35 publications

(45 citation statements)

References 66 publications

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“…3G). This subcellular distribution is similar to observations made on mouse hair cells (20,23,37). Probing 120-h wild-type zebrafish with the FM1-43 dye (Fig.…”

Section: Zebrafish Have Two Copies Of Otoferlinsupporting

confidence: 86%

“…Indeed, the loss in hearing we observed in otoferlin knockdown zebrafish matches mouse knockout models. We also note that while zebrafish have two otoferlin genes and mammals have one, multiple splice isoforms of the gene have been reported for mice and humans (23,50).…”

Section: Discussionmentioning

confidence: 64%

“…Otoferlin is a six-C2 domain transmembrane protein expressed in inner, outer, and vestibular hair cells, as well as restricted regions of the brain (13-16). In humans, missense mutations in otoferlin have been linked to hearing loss (17,18), and biochemical studies have determined that otoferlin binds calcium and lipids (12,19), as well as membrane trafficking proteins (12,(20)(21)(22)(23). Further, in vitro assays have demonstrated that otoferlin accelerates SNARE-mediated membrane fusion (12).…”

Section: Sensory Hair Cells Convert Mechanical Motion Into Chemical Smentioning

confidence: 99%

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Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Chatterjee

Padmanarayana

Abdullah

et al. 2015

Molecular and Cellular Biology

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Sensory hair cells convert mechanical motion into chemical signals.Otoferlin, a six-C2 domain transmembrane protein linked to deafness in humans, is hypothesized to play a role in exocytosis at hair cell ribbon synapses. To date, however, otoferlin has been studied almost exclusively in mouse models, and no rescue experiments have been reported. Here we describe the phenotype associated with morpholino-induced otoferlin knockdown in zebrafish and report the results of rescue experiments conducted with full-length and truncated forms of otoferlin. We found that expression of otoferlin occurs early in development and is restricted to hair cells and the midbrain. Immunofluorescence microscopy revealed localization to both apical and basolateral regions of hair cells. Knockdown of otoferlin resulted in hearing and balance defects, as well as locomotion deficiencies. Further, otoferlin morphants had uninflated swim bladders. Rescue experiments conducted with mouse otoferlin restored hearing, balance, and inflation of the swim bladder. Remarkably, truncated forms of otoferlin retaining the C-terminal C2F domain also rescued the otoferlin knockdown phenotype, while the individual N-terminal C2A domain did not. We conclude that otoferlin plays an evolutionarily conserved role in vertebrate hearing and that truncated forms of otoferlin can rescue hearing and balance.H air cells couple mechanical motion to neurotransmitter release at synapses (1). In contrast to conventional neural synapses, hair cell synapses release neurotransmitter continuously and, in a graded manner (2), possess synaptic ribbons (2-4), and lack synaptophysin (5), complexin (6-9), Munc13 (10), and the calcium sensors synaptotagmin I and II (11). In place of synaptotagmin, it is believed that otoferlin may confer calcium sensitivity to evoke neurotransmitter release (12, 13). Otoferlin is a six-C2 domain transmembrane protein expressed in inner, outer, and vestibular hair cells, as well as restricted regions of the brain (13-16). In humans, missense mutations in otoferlin have been linked to hearing loss (17,18), and biochemical studies have determined that otoferlin binds calcium and lipids (12,19), as well as membrane trafficking proteins (12,(20)(21)(22)(23). Further, in vitro assays have demonstrated that otoferlin accelerates SNARE-mediated membrane fusion (12). Based upon this evidence, it is hypothesized that otoferlin functions as a calcium-sensitive regulator of neurotransmitter release in sensory hair cells.However, the results of several studies have raised questions related to otoferlin's function. For instance, despite otoferlin expression in vestibular hair cells, knockout mice show no balance defects (24, 25) despite reduced exocytosis in vestibular type I hair cells (24,26). This raises questions as to the importance of otoferlin in this system. Further, otoferlin did not rescue synchronous neurotransmitter release in synaptotagmin I knockout cultured neurons, indicating that otoferlin and synaptotagmin are not functionally redundant (2...

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“…3G). This subcellular distribution is similar to observations made on mouse hair cells (20,23,37). Probing 120-h wild-type zebrafish with the FM1-43 dye (Fig.…”

Section: Zebrafish Have Two Copies Of Otoferlinsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 64%

Section: Sensory Hair Cells Convert Mechanical Motion Into Chemical Smentioning

confidence: 99%

See 1 more Smart Citation

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Chatterjee

Padmanarayana

Abdullah

et al. 2015

Molecular and Cellular Biology

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“…Otoferlin, a member of the ferlins family (reviewed in [34]), contain multiple C2 domains, and is known to be the Ca 2+ -sensor involved in SNARE-mediated synaptic release that controls hearing [35]. Single-cell repair has also been shown to involve exocytosis; SNARE complexes, and members of the synaptotagmin and ferlin families have also been shown to be involved in membrane resealing.…”

Section: C2-domain Containing Proteinsmentioning

confidence: 99%

“…In mammalian cells, Rho GTPases could also be recruited by AHNAK upon the Ca 2+ -dependent exocytosis of enlargeosomes, as AHNAK has been shown to be able to activate PKC A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 35 through dissociation of the PKC-protein phosphatase 2A complex [188]. Similarly, formation of ceramide-rich membrane domains may also leads to Rho GTPases helping in F-actin remodeling.…”

Section: Hypotheses and Future Perspectivesmentioning

confidence: 99%

Plasma membrane and cytoskeleton dynamics during single-cell wound healing

Boucher

Mandato

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Wounding leads not only to plasma membrane disruption, but also to compromised cytoskeleton structures. This results not only in unwarranted exchanges between the cytosol and extracellular milieu, but also in loss of tensegrity, which may further endanger the cell. Tensegrity can be described as the interplay between the tensile forces generated by the apparent membrane tension, actomyosin contraction, and the cytoskeletal structures resisting those changes (e.g., microtubules). It is responsible for the structural integrity of the cell and for its ability to sense mechanical signals. Recent reviews dealing with single-cell healing mostly focused on the molecular machineries controlling the traffic and fusion of specific vesicles, or their role in different pathologies. In this review, we aim to take a broader view of the different modes of single cell repair, while focussing on the different ways the changes in plasmalemma surface area and composition, plasmalemma tension, and cytoskeletal dynamics may influence and affect single-cell repair.

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Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses

Pangršič

Vogl

2018

FEBS Letters

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The timely and reliable processing of auditory and vestibular information within the inner ear requires highly sophisticated sensory transduction pathways. On a cellular level, these demands are met by hair cells, which respond to sound waves – or alterations in body positioning – by releasing glutamate‐filled synaptic vesicles (SVs) from their presynaptic active zones with unprecedented speed and exquisite temporal fidelity, thereby initiating the auditory and vestibular pathways. In order to achieve this, hair cells have developed anatomical and molecular specializations, such as the characteristic and name‐giving ‘synaptic ribbons’ – presynaptically anchored dense bodies that tether SVs prior to release – as well as other unique or unconventional synaptic proteins. The tightly orchestrated interplay between these molecular components enables not only ultrafast exocytosis, but similarly rapid and efficient compensatory endocytosis. So far, the knowledge of how endocytosis operates at hair cell ribbon synapses is limited. In this Review, we summarize recent advances in our understanding of the SV cycle and molecular anatomy of hair cell ribbon synapses, with a focus on cochlear inner hair cells.

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Calcium Regulates Molecular Interactions of Otoferlin with Soluble NSF Attachment Protein Receptor (SNARE) Proteins Required for Hair Cell Exocytosis

Cited by 35 publications

References 66 publications

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Plasma membrane and cytoskeleton dynamics during single-cell wound healing

Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses

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